[go: up one dir, main page]

US11529341B2 - Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation - Google Patents

Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation Download PDF

Info

Publication number
US11529341B2
US11529341B2 US16/980,284 US201916980284A US11529341B2 US 11529341 B2 US11529341 B2 US 11529341B2 US 201916980284 A US201916980284 A US 201916980284A US 11529341 B2 US11529341 B2 US 11529341B2
Authority
US
United States
Prior art keywords
alkyl
methyl
methoxy
cycloalkyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US16/980,284
Other languages
English (en)
Other versions
US20210015810A1 (en
Inventor
Chandregowda Venkateshappa
Jeyaraj D A
Muralidhar Pendyala
Dhanalakshmi Sivanandhan
Sridharan Rajagopal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jubilant Prodel LLC
Original Assignee
Jubilant Prodel LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jubilant Prodel LLC filed Critical Jubilant Prodel LLC
Publication of US20210015810A1 publication Critical patent/US20210015810A1/en
Assigned to Jubilant Prodel LLC reassignment Jubilant Prodel LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PENDYALA, Muralidhar, VENKATESHAPPA, Chandregowda, D A, Jeyaraj, RAJAGOPAL, SRIDHARAN, SIVANANDHAN, Dhanalakshmi
Application granted granted Critical
Publication of US11529341B2 publication Critical patent/US11529341B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to substituted bicyclic compounds of Formula I along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof which are inhibitors of PD1/PD-L1 interaction.
  • the present invention also relates to method of synthesizing the compounds of Formula I.
  • the compounds described herein are inhibitors of PD1/PD-L1 activation and may be used in the treatment of cancer, and other diseases or conditions associated with activation of PD1/PD-L1.
  • Tumour development and survival involves the interplay between cancer cells, normal stromal cells and host defence mechanisms (Vinay D. S. et al., Seminars in Cancer Biology, 2015, 35: S185-S198).
  • CTLs cytotoxic T cells
  • Th1 CD4+ helper T cells curb cancer development via mechanisms commonly involving the production of interferon (IFN)- ⁇ and cytotoxins (Zamarron B F et al., Intl. J. Biol. Sciences, 2011, 7(5):651-658).
  • Tumours have, however evolved a number of mechanisms to escape immune eradications.
  • the PD-1/PD-L1 molecular pathway is one such primary mechanism of cancer immune evasion.
  • PD-1 is a type 1 trans-membrane protein encoded by the PDCD1 gene. It is a member of the extended CD28/CTLA-4 immunoglobulin family and one of the most important inhibitory co-receptors expressed by T cells (He J. et al., Scientific Reports, 2015, 5:1-9). PD-1 is absent on resting T cells but is induced on activated T cells. It is also expressed on B cells, NK cells, dendritic cells (DCs) and macrophages. The programmed cell death protein (PD-1) down regulates the immune system and prevents it from killing cancerous cells present in the body. In cancer, high levels of PD-1 are detected in tumour infiltrating T cells and this expression has been associated with impaired CD8+ T cell function (Leung J et al., Immune Network, 2014, 14(6):265-276).
  • PD-1 has two ligands: PD-L1 (also named B7-H1; CD274) and PD-L2 (B7-DC; CD273), that are both co-inhibitory (Flies D. B. et al., Yale J. Biology Medicine, 2011, 84(4):409-421).
  • PD-L1 expressed on almost all murine tumour cells, is the major ligand for PD-1 mediated immune suppression. It is constitutively expressed on APCs and can be broadly induced on cells in both lymphoid tissues and non-lymphoid peripheral tissues following cellular activation (Flies D. B. et al., Yale J. Biology Medicine, 2011, 84(4):409-421; Dong Y.
  • the cytokine IFN- ⁇ is particularly effective in up-regulating PD-L1 expression due to IFN- ⁇ response elements in the PD-L1 promoter region (Lee S. J. et al., FEBS Letters, 2006, 580:755-762; Flies D. B. et al., Immunotherapy, 2007, 30(3):251-260).
  • the expression of B7-DC/PD-L2 is largely restricted to myeloid dendritic cells (DCs) and macrophages in lymphoid compartments and is not broadly expressed in peripheral tissues (Flies D. B. et al., Yale J. Biology Medicine, 2011, 84(4):409-421).
  • PD-L1 is expressed on the surface of tumour cells in various solid malignancies such as squamous cell carcinoma of the head and neck, melanoma, carcinomas of the brain, thyroid, thymus, esophagus, lung, breast, gastrointestinal tract, colorectum, liver, pancreas, kidney etc.
  • solid malignancies such as squamous cell carcinoma of the head and neck, melanoma, carcinomas of the brain, thyroid, thymus, esophagus, lung, breast, gastrointestinal tract, colorectum, liver, pancreas, kidney etc.
  • Cancer microenvironment manipulates the PD-1/PD-L1 pathway; induction of PD-L1 expression is associated with inhibition of immune responses against cancer, thus permitting cancer progression and metastasis (He J. et al., Scientific Reports, 2015, 5:1-9; Bardhan K. et al., Frontiers in Immunology, 2016, 7(550):1-17).
  • Activation of PD-1/PD-L1 pathway induces apoptosis of activated T cells (Dong H. et al., Nature Medicine, 2002, 8(8):793-800; Curiel T. J. et al., Nature Medicine, 2003, 9(5):562-567), facilitates T cell anergy and exhaustion (Barber D. L.
  • Blockade of the PD-1/PD-L1 pathway by therapeutic antibodies has been shown to prevent inhibitory signalling from cancer cells and enabling CTLs to elicit an immune response against the target/cancer cells (Zou W. et al., Sci. Transl. Med., 2016, 8(328):328rv4; Smahel M., Int. J. Mol. Sci., 2017, 18(6):1331).
  • a number of cancer immunotherapy agents targeting PD-1 have been developed till date and approved for a number of malignancies including melanoma, lung cancer, kidney cancer, Hodgkin's lymphoma, head and neck cancer and urothelial cancer.
  • the first therapeutic anti-PD-L1 antibody was approved by the FDA in May 2016, for the treatment of patients with metastatic urothelial carcinoma and non-small cell lung cancer, with a number of additional therapies in the pipeline.
  • PD-1/PD-L1 antibodies against 20 types of solid and haematological malignant tumours.
  • potent and selective small molecule inhibitors of the PD-1/PD-L1 pathway are also known.
  • AEs drug-related adverse effects
  • irAEs Immune-related AEs
  • irAEs dermatitis, colitis, hepatitis, vitiligo and thyroiditis have been reported and about 10% of patients develop grade 3 or 4 irAEs (Hamanishi J. et al., Int. J. Clin. Oncol., 2016, 21:462-473).
  • the long residence time of the monoclonal antibodies (mAbs) could contribute to these AEs, which may be partially circumvented using a small molecule inhibitor.
  • the PD-1/PD-L1 inhibitory compounds have vast utility in up-regulating the immune system for efficiently combating cancer. Therefore, the identification of a chemical moiety, especially small molecule inhibitors, that facilitates this inhibition is necessary. Therefore, the identification and development of new PD-1/PD-L1 inhibitor compounds treating cancer and other diseases or conditions associated with activation of PD-1/PD-L1 would open new opportunities in the realm of cancer treatment.
  • X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—;
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl;
  • X is selected from CR 3 or N;
  • X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 5 is selected from C 1-4 alkyl, cyano,
  • X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl; wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 5 is selected from C 1-4 alkyl, cyano,
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 1 , R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a ,
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl
  • C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl
  • R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl
  • R 1 , R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, halo
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl
  • C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl
  • R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl
  • R 1 , R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, halo
  • the present disclosure further describes the process of preparation of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof.
  • the present disclosure also discloses the method for the treatment and/or prevention of various diseases, including cancer and infectious diseases, comprising administering to a subject suffering from the proliferative disorder or cancer a therapeutically effective amount of the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition comprising compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, with other clinically relevant cytotoxic agents or non-cytotoxic agents to a subject in need thereof.
  • the present disclosure further discloses the use of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition comprising compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, for the treatment and/or prevention of various diseases including proliferative disorder or cancer; or treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents.
  • the present disclosure also discloses a method for the treatment of cancer, said method comprising administering a combination of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition comprising compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, with other clinically relevant cytotoxic agents or non-cytotoxic agents to a subject in need thereof.
  • the present disclosure further describes a method of treatment of cancer, said method comprising administering a combination of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or the pharmaceutical composition, with other clinically relevant immune modulators agents to a subject in need of thereof.
  • the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI can be its derivatives, analogs, stereoisomers, diastereomers, geometrical isomers, polymorphs, solvates, co-crystals, intermediates, metabolites, prodrugs or pharmaceutically acceptable salts and compositions.
  • the compounds according to Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI may contain one or more asymmetric centers (also referred to as a chiral centers) and may, therefore, exist as individual enantiomers, diastereoisomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • compounds according to Formula I-VI containing one or more chiral centers may be used as racemic modifications including racemic mixtures and racemates, enantiomerically-enriched mixtures, or as enantiomerically-pure individual stereoisomers.
  • Compounds disclosed herein include isotopes of hydrogen, carbon, oxygen, fluorine, chlorine, iodine and sulfur which can be incorporated into the compounds, such as not limited to 2 H (D), 3 H (T), c 11 C, 13 C, 14 C, 15 N, 18 F, 35 S, 36 Cl and 125 I.
  • Compounds of this invention where in atoms were isotopically labeled for example radioisotopes such as 3 H, 13 C, 14 C, and the like can be used in metabolic studies and kinetic studies.
  • Compounds of the invention where hydrogen is replaced with deuterium may improve the metabolic stability and pharmacokinetics properties of the drug such as in vivo half life.
  • Individual stereoisomers of a compound according to Formula I-VI which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • references herein to compounds of Formula I-VI and salts thereof covers the compounds of Formula I-VI as free bases, or as salts thereof, for example as pharmaceutically acceptable salts thereof.
  • the invention is directed to compounds of Formula I-VI as the free base.
  • the invention is directed to compounds of Formula I-VI and salts thereof.
  • the invention is directed to compounds of Formula I-VI and pharmaceutically acceptable salts thereof.
  • pharmaceutically acceptable salts of the compounds according to Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds according to Formula I-VI may be preferred over the respective free base because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to compounds of Formula I-VI, and pharmaceutically acceptable salts thereof.
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or non-crystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, isopropyl alcohol, dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Hydrates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as “hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphs may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs”.
  • the invention includes such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • polymorphs refers to crystal forms of the same molecule, and different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice.
  • substituted in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as rearrangement, cyclisation, or elimination). In certain embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.
  • prodrugs refers to the precursor of the compound of Formula Ia, and Formula I which on administration undergoes chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of a compound of the invention, which are readily convertible in vivo into a compound of the invention.
  • alkyl refers to a saturated hydrocarbon chain having the specified number of carbon atoms.
  • C 1-6 alkyl refers to an alkyl group having from 1-6 carbon atoms, or 1-4 carbon atoms.
  • Alkyl groups may be straight or branched chained groups. Representative branched alkyl groups have one, two, or three branches.
  • Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, and t-butyl.
  • alkoxy refers to an alkyl group attached via an oxygen linkage to the rest of the molecule.
  • C 1-6 alkoxy refers to an alkyl group having from 1-6 carbon atoms, or 1-4 carbon atoms attached via an oxygen linkage to the rest of the molecule.
  • Preferred alkoxy groups include, without limitation, —OCH 3 (methoxy), —OC 2 H 5 (ethoxy) and the like.
  • haloalkyl refers to a halogen in an alkyl group as defined above attached via alkyl linkage to the rest of the molecule.
  • C 1-6 haloalkyl refers to an alkyl group having from 1-6 carbon atoms, or 1-4 carbon atoms wherein one or more hydrogen atoms are replaced by the same number of identical or different halogen atoms.
  • Preferred haloalkyl groups include, without limitation, —CH2Cl, —CHCl2, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.
  • haloalkoxy refers to a halogen in an alkoxy group as defined above further attached via oxygen linkage to the rest of the molecule.
  • C 1-6 haloalkoxy refers to an alkoxy group having from 1-6 carbon atoms, or 1-3 carbon atoms further attached via halo linkage.
  • Preferred haloalkoxy groups include, without limitation, —OCH 2 Cl, —OCHCl 2 , and the like.
  • halo or halogen refers to a halogen radical, for example, fluoro, chloro, bromo, or iodo.
  • cycloalkyl refers to a saturated hydrocarbon ring having a specified number of carbon atoms, which may be monocyclic or polycyclic.
  • C 3-10 cycloalkyl refers to a cycloalkyl group having from 3 to 10 member atoms or 3 to 6 member atoms.
  • the polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures.
  • C 3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 membered atoms.
  • Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, perhydronaphthyl, adamantyl, noradamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl, and the like.
  • aryl refers to aromatic ring having a specified number of carbon atoms.
  • C 5-6 aryl refers to an aryl group having 5 or 6 member atoms, or 6 member atoms.
  • C 6-10 aryl refers to an aryl group having 6 to 10 member atoms.
  • Preferred aryl groups include, without limitation, phenyl, and the like.
  • heteroaryl refers to aromatic rings containing from 1 to 3 heteroatoms in the ring. “Heteroaryl” groups may be substituted with one or one or more substituents if so defined herein.
  • the “C 1-6 heteroaryl” rings having 1 or 6 carbon as member atoms.
  • the term “5-14 membered heteroaryl” has 5 to 14 carbon as member atoms.
  • the “heteroaryl” includes pyridinyl, tetrazolyl and pyrazolyl.
  • Heteroatom refers to a nitrogen, sulfur, or oxygen atom, for example a nitrogen atom or an oxygen atom.
  • heterocyclic or refer to saturated or unsaturated monocyclic aliphatic rings containing 5, 6, or 7 ring members including 1-3 heteroatoms or to saturated or unsaturated bicyclic, tricyclic, tetracyclic aliphatic rings containing 5, 6 or 7 ring members including 1-3 heteroatoms, which may include spiro, fused, or bridged ring systems.
  • “heterocyclic” groups are saturated. In other embodiments, “heterocyclic” groups are unsaturated. “heterocyclic” groups containing more than one heteroatom may contain different heteroatoms. “heterocyclic” groups may be substituted with one or more substituents as defined herein.
  • heterocyclic includes piperidinyl, tetrahydropyranyl, azepinyl, oxazepinyl, azabicyclo[3.1.0]hexanyl.
  • heterocycloalkyl- refers to to a heterocyclic group as defined above further attached via alkyl linkage to the rest of the molecule.
  • 4-10 membered heterocycloalkyl refers to heterocyclic group as defined above further attached via alkyl linkage to the rest of the molecule.
  • phrases “pharmaceutically acceptable” refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable acid.
  • Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and their pharmaceutically acceptable salts.
  • one embodiment of the invention embraces compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, and salts thereof.
  • Compounds according to and Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids.
  • Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenyl acetate, propionate, butyrate, iso-butyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate
  • PD-1/PD-L1 inhibitor or inhibitory compounds or “inhibitors of PD-1/PD-L1 activation” is used to identify a compound, which is capable of blocking PD-1/PD-L1 pathway to prevent inhibitory signalling from cancer cells and enabling CTLs to elicit an immune response against the target/cancer cells and thus treat cancer and other diseases or conditions associated with activation of PD1/PD-L1.
  • cytotoxic agents or “inhibitors” is used to identify any agents or drugs which are capable of killing cells including cancer cells. These agents or 10 inhibitors may stop cancer cells from growing and dividing and may cause tumors to shrink in size.
  • non-cytotoxic agents or “inhibitors” is used to identify any agents or inhibitors are which does not directly kill cells, but instead affects cellular transport and metabolic functions to ultimately produce cell death.
  • immune checkpoint inhibitors agents or “immune modulators agents” are used to identify any agents or inhibitors that blocks certain proteins made by some types of immune system cells, such as T cells, and some cancer cells. These proteins help keep immune responses in check and can keep T cells from killing cancer cells.
  • the immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1B), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.
  • immune modulators agents and “immune checkpoint inhibitors” are used interchangeably throughout the present disclosure.
  • X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—;
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl;
  • X is selected from CR 3 or N;
  • a compound of Formula I having polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—; R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alky
  • R d is selected from cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R
  • X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 5 is selected from C 1-4 alkyl, cyano,
  • a compound of Formula II having polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—; R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alky
  • R f is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, halogen, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , NR g C(O)R g
  • X 1 is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl; wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 5 is selected from C 1-4 alkyl, cyano,
  • a compound of Formula III having polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein X 1 is selected from —CH 2 O—, —OCH 2 —, or —C(O)NH—; R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl; wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 5 is selected from C
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 1 , R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a ,
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 3 is independently selected from hydrogen, halo, C(O)OR a , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, or C 3-10 cycloalkyl
  • R 1 , R 2 , R 6 , and R 7 are independently selected from hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl
  • C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl
  • R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl
  • R 1 , R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, halo
  • a compound of Formula V having polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl; R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 3 is independently selected from hydrogen, halo, C(O)OR a , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, or C 3-10 cycloalkyl; R 1 , R 2 , R 6 , and R 7 are independently selected from hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 al
  • R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl
  • R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl
  • C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl
  • R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl
  • R 1 , R 2 , R 3 , R 6 , and R 7 are independently selected from hydrogen, halo
  • a compound of Formula VI having polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, wherein R 5 is selected from C 1-4 alkyl, cyano, or C 1-4 haloalkyl; R 4 is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino; R a1 , R b1 , and R c1 are independently selected from hydrogen or C 1-6 alkyl; R 3 is independently selected from hydrogen, halo, C(O)OR a , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, or C 3-10 cycloalkyl; R 1 , R 2 , R 6 , and R 7 are independently selected from hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 al
  • the present disclosure relates to compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof, which is selected from a group consisting of:
  • the present disclosure relates to a process of preparation of compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, and Formula VI as described herein, or its polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof.
  • the present disclosure relates to a process of preparation of Formula I, comprising steps of: (a) reacting compounds of Formula I (a) with substituted amines to obtain compounds of Formula I
  • the present disclosure relates to a process of preparation of Formula I, comprising steps of: (a) reacting compounds of Formula I (a), wherein the X 1 of Formula I (a) and Formula I is selected from —CH 2 O—, —OCH 2 —, —C(O)NH— or —NHC(O)—; R 4 of Formula I (a) and Formula I is selected from hydrogen, hydroxyl, C 1-6 alkyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, or C 1-6 heteroaryl, wherein C 1-6 alkyl is optionally substituted with one or more of the groups selected from the group consisting of hydrogen, hydroxyl, amino, —C(O)OR a1 , C(O)NR b1 R c1 , C 5-6 aryl, and C 1-6 heteroaryl; R a1 , R b1 , and R c1 are independently selected from hydrogen
  • the present disclosure relates to pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or Formula II, or Formula III, or Formula IV, or Formula V, or Formula VI as described herein, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • the present disclosure relates to the pharmaceutical composition as described herein, wherein the composition is in the form selected from the group consisting of a tablet, capsule, powder, syrup, solution, aerosol and suspension.
  • inorganic bases such as like Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn
  • salts of organic bases such as N, N′-diacety
  • Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, and guanidine.
  • Salts may include acid addition salts where appropriate which are sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates.
  • the present disclosure relates to a method for the treatment and/or prevention of a proliferative disorder or cancer comprising administering to a subject suffering from the proliferative disorder or cancer a therapeutically effective amount of the compounds of Formula I, or Formula II, or Formula III, or Formula IV, or Formula V, or Formula VI or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, with other clinically relevant cytotoxic agents or non-cytotoxic agents to a subject in need thereof.
  • the present disclosure relates to the use of compounds of Formula I, or Formula II, or Formula III, or Formula IV, or Formula V, or Formula VI or a pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier, for the treatment and/or prevention of a proliferative disorder or cancer; or treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents.
  • the present disclosure relates to the use of compounds of Formula I, or Formula II, or Formula III, or Formula IV, or Formula V, or Formula VI or pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier, for the treatment and/or prevention of various diseases including proliferative disorder or cancer; or treatment of cancer together with other clinically relevant cytotoxic agents or non-cytotoxic agents, wherein 30 the other clinically relevant cytotoxic agents or non-cytotoxic agents are selected from the group consisting of carboplatin, bortezomib, carfilzomib, lenalidomide, pomalidomide, doxorubicin, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate cyclophosphamide, 5-fluorouracil, imatinib, methotrexate, irinotecan, top
  • the present disclosure relates to a method for the treatment of cancer as described herein, wherein said method comprising administering a combination of the compounds of Formula I, or Formula II, or Formula III, or Formula IV, or Formula V, or Formula VI or a pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier, with other clinically relevant cytotoxic agents or non-cytotoxic agents to a subject in need thereof.
  • a method of treatment and/or prevention of various diseases comprising administering to a subject suffering from the viral infectious diseases such as HIV, Influenza, herpes virus, Hepatitis A, Hepatitis B, Hepatitis C, and Hepatitis D, a therapeutically effective amount of the compound of Formula I, Formula II, Formula III, Formula IV Formula V and Formula VI or the pharmaceutical composition, with other clinically relevant anti-viral drugs to a subject in need thereof.
  • the viral infectious diseases such as HIV, Influenza, herpes virus, Hepatitis A, Hepatitis B, Hepatitis C, and Hepatitis D
  • a therapeutically effective amount of the compound of Formula I, Formula II, Formula III, Formula IV Formula V and Formula VI or the pharmaceutical composition with other clinically relevant anti-viral drugs to a subject in need thereof.
  • the present disclosure relates to a method of treatment of cancer as described herein, wherein said method comprising administering a combination of the compounds of Formula I, or Formula II, or Formula III, or Formula IV, or Formula V, or Formula VI or the pharmaceutical composition with other clinically relevant immune modulators agents to a subject in need of thereof.
  • C18 Refers to 18-carbon alkyl groups on silicon in HPLC stationary phase
  • DIPEA Hünig's base N-ethyl-N-(1-methylethyl)-2-propanamine
  • the compounds of the invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out in the following schemes and can be readily adapted to prepare other compounds of the invention.
  • Compound B was prepared from dimethoxy phenyl propionic acid A, by reacting with polyphosphoric acid. Selective demethylation of compound B was performed using BBr 3 to obtain compound C. Upon decarbonylation of C using reducing agent compound D was obtained. Formylation of compound D using dichloro(methoxy)methane and titanium tetrachloride yielded compound E. O-alkylation of E using substituted biphenyl methyl bromides E1 gave compound F. In some cases of the present invention instead of biphenyl methyl bromide E1, biphenyl methyl alcohol E1a was used and followed by Mitsunobu reaction conditions to give intermediate F.
  • the unsubstituted indane core was prepared according to Scheme-2.
  • Decarbonylation of G was performed using trifluoroacetic acid and triethylsilane to obtain intermediate H.
  • Subsequent steps were performed following the procedure described in scheme-1 to obtain compounds of the general formula V and VI.
  • Biphenyl methyl bromides (E1) or corresponding alcohols were prepared by following Suzuki coupling reaction using corresponding substituted phenyl boronic acid and substituted bromo benzene.
  • Halogen-substituted indane derivatives were prepared according to scheme-4. Decarbonylation of 4-hydroxy-2,3-dihydro-1H-inden-1-one S followed by chlorination gave 5-chloro-2,3-dihydro-1H-inden-4-ol U. Intermediate U was formylated to give 6-chloro-7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde V. Subsequent steps were performed following the procedure described in Scheme-1 to obtain compounds of the general formula VI.
  • Ester-substituted indane derivatives were prepared according to scheme-5. O-alkylation of 4-hydroxy-2,3-dihydro-1H-indene-5-carbaldehyde gave intermediate Y. Oxidation of aldehyde to acid using sodium dihydrogen phosphate and hydrogen peroxide gave intermediate Z. Intermediate Z was converted to corresponding ester Z1 using methyl iodide in presence of potassium carbonate. Intermediate Z1 was treated with TFA and hexamine to give benzyl de-protected aldehyde compound methyl 7-formyl-4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate Z2. Subsequent steps were performed following the procedure described in Scheme-1 to obtain compounds of the general formula VI.
  • Nitrogen containing bicyclic heterocyclic compounds of the Formula I are prepared according to Scheme-7. Reacting cyclopentanone with malanonitrile and carbondisulphide gave bicyclic heterocycle intermediate E11. Hydrolysis and decarboxylation was performed using base to give E12. Methylation of thiol group using base and methyl iodide and O-alkylation using alkyl halide in presence of silveroxide or base gave intermediate E14. Bromination gave intermediate E15. Sulfoxidation of E15 gave intermediate E16. Nucleophilic displacement of E6 with E1a resulted with intermediate E17. Bromo to vinyl conversion was performed by Stille coupling, vinyl group was oxidized to aldehyde to give E19. Reductive amination of E19 with different amines resulted compounds of the general Formula I.
  • Step 1 A stirred solution of 5-bromonicotinonitrile (22 g, 0.120 mol) and tributyl vinyl tin (95.3 g, 0.300 mol) in DMF (200 mL) was purged with nitrogen for 10 min. To this mixture, Pd(PPh 3 ) 4 (13.84 g, 0.012 mol) was added and purged again with nitrogen for 20 min. Then the mixture was heated at 80° C. for 4 h. After completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 ⁇ 200 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step-2 To a stirred solution of 5-vinylnicotinonitrile (10.5 g, 0.081 mol) in acetone (200 mL) and water (40 mL) at 0° C., OsO 4 (82 mL, 2.5 wt % solution in tert-butanol, 0.0081 mol) and N-Methylmorpholine N-oxide (29 g, 0.242 mol) were added and stirred for 3 h. To this mixture, NaIO 4 (60 g, 0.282 mol) was added and the reaction mixture was allowed to stir at room temperature for 12 h.
  • OsO 4 82 mL, 2.5 wt % solution in tert-butanol, 0.0081 mol
  • N-Methylmorpholine N-oxide 29 g, 0.242 mol
  • Step-3 To a stirred solution of 5-formylnicotinonitrile (12 g, 0.091 mol) in methanol (100 mL) at 0° C., sodium borohydride (5.12 g, 0.136 mol) was added portion wise for 30 minutes and stirred the mixture at 0° C. for 2 h. The reaction mixture was concentrated and the residue was diluted with water (100 mL) and DCM (200 mL). The organic layer was dried over sodium sulfate and concentrated. The crude was purified by column chromatography (silica gel, 100-200 mesh) using 1% MeOH in DCM to obtain 5-(hydroxymethyl)nicotinonitrile as yellow solid (Yield: 7.4 g, 60.7%).
  • Step-4 To a stirred solution of 5-(hydroxymethyl)nicotinonitrile (3 g, 0.022 mol) in DCM (30 mL), 4M HCl in 1,4-dioxane (5 mL) was added and concentrated the mixture under vacuum. To the resulting residue, thionyl chloride (20 mL) was added and stirred the mixture at 60° C. for 3 h. After completion, the reaction was cooled to room temperature and diluted with toluene (150 mL) and filtered off the solid that precipitated out. The filtrate was diluted with DCM (200 mL) and washed with saturated sodium bicarbonate solution (200 mL).
  • Step-1 A solution of 2-amino-3-bromobenzoic acid (10.0 g, 0.046 mol) in dry THF (100 mL) at 0° C., borane-DMS (118 mL, 1M in THF, 5 eq) was added and stirred the mixture at room temperature for 24 h. After completion, the reaction was quenched with methanol (20 mL) and concentrated under vacuum.
  • Step-2 A solution of (2-amino-3-bromophenyl)methanol (9.70 g, 0.048 mol) and phenyl boronic acid (7.65 g, 0.062 mol) in water (60 mL), toluene (60 mL) and methanol (70 mL) was degassed with nitrogen gas for 15 minutes. To this mixture, Pd(PPh 3 ) 2 Cl 2 (3.37 g, 0.0048 mol) and sodium carbonate (13.4 g, 0.127 mol) were added and stirred the mixture at 80° C. for 8 h. After completion, the mixture was filtered over celite and washed with EtOAc (2 ⁇ 200 mL).
  • Step-3 To a solution of (2-amino-[1,1′-biphenyl]-3-yl)methanol (2.5 g, 12.5 mmol) in water (15 mL) and toluene (15 mL), conc.HCl (6 mL) was added and cooled the mixture to 0° C. To this mixture, a solution of sodium nitrite (1.7 g, 18.8 mmol) in water (5 mL) was added slowly and continued stirring at 0° C. for 1.5 h. The pH of the solution was adjusted to 6.0 using sodium carbonate solution.
  • This diazonium solution was added slowly to a solution of CuSO 4 (2.3 g, 15 mmol) and sodium cyanide (3.07 g, 62.5 mmol) in water (15 mL) and toluene (15 mL) at 60° C. After stirring at 60° C. for 2 h, the reaction mixture was cooled to room temperature and filtered and washed with EtOAc (100 mL). The organic layer of the filtrate was washed with brine (20 mL) and concentrated.
  • Step-4 To a stirred solution of 3-(hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile (3.5 g, 16.7 mmol) in DCM (50 mL) at 0° C., triphenyl phosphine (6.5 g, 25.1 mmol) and carbon tetrabromide (8.31 g, 25.1 mmol) were added and allowed to stir at room temperature for 4 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3 ⁇ 200 mL). The organic layer was dried over sodium sulfate and concentrated.
  • Step-1 To a stirred solution of methyl 5-fluoronicotinate (9.2 g, 59 mmol) in dry THF (40 mL) under nitrogen atmosphere at ⁇ 78° C., a 2.5 M solution of LiAlH 4 in THF (31 mL, 77 mmol) was added drop wise and allowed the mixture to stir at same temperature for 40 minutes. After completion, the reaction was quenched at same temperature with saturated ammonium chloride (10 mL) and poured into ice cold water (100 mL).
  • Step-2 To a solution of (5-fluoropyridin-3-yl)methanol (0.5 g, 3.93 mmol) in DCM (20 mL) at 0° C., triethylamine (1.63 mL, 11.80 mmol) and p-tosylchloride (2.24 g, 5.90 mmol) were added and then allowed the mixture to stir at room temperature for 6 h. The reaction mixture was diluted with water (25 mL) and extracted with DCM (3 ⁇ 40 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated.
  • Step-1 To a solution of tert-butyl (2-aminoethyl)(methyl)carbamate (4.2 g, 25.7 mmol) in ethanol (60 mL), N-hydroxyphthalimide (4.50 g, 25.7 mmol) was added and stirred the mixture at 60° C. for 6 h. After completion, concentrated the mixture under vacuum. The residue was washed with diethyl ether (2 ⁇ 10 mL) to obtain tert-butyl (2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (Yield: 5.8 g, 74%) as white solid.
  • Step-2 To a solution of tert-butyl (2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (6 g, 19.7 mmol) in 1,4-dioxane (100 mL), 4M HCl in 1,4-dioxane (50 mL) was added and stirred the mixture at room temperature for 3 h. After completion, concentrated the mixture under vacuum. The resulting residue was washed with diethyl ether (2 ⁇ 10 mL) to obtain HCl salt of 2-(2-(methylamino)ethyl)isoindoline-1,3-dione (Yield: 4.0 g, 98%) as white solid.
  • Step-3 To a solution of 2-(2-(methylamino)ethyl)isoindoline-1,3-dione (3.5 g, 17.1 mmol) in DMF (40 mL), triethylamine (5.2 g, 51.3 mmol) and acetyl chloride (2 g, 25 mmol) were added and stirred for 2 h at room temperature. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 ⁇ 100 mL). The organic layer was dried over sodium sulfate and concentrated.
  • Step-4 To a solution of N-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-methylacetamide (2.2 g, 8.93 mmol) in ethanol (30 mL), hydrazine hydrate (0.58 g, 11.6 mmol) was added and stirred the mixture for 6 h at room temperature. After completion, the mixture was concentrated. The resulting residue was diluted with pentane (50 mL) and filtered. Concentration of the filtrate provided N-(2-aminoethyl)-N-methylacetamide (Yield: 106 mg, 10.2%) as an oil.
  • Step-1 To a stirred solution of 3-acetylbenzonitrile (2.0 g, 13.7 mmol) in methanol (30 mL), sodium borohydride (0.62 g, 15.5 mmol) was added and stirred at room temperature for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The organic layer was dried and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 20% EtOAc in hexanes to obtain 3-(1-hydroxyethyl)benzonitrile (Yield: 1.8 mg, 91%) as colourless liquid.
  • Step-2 To a stirred solution of 3-(1-hydroxyethyl)benzonitrile (1.0 g, 6.8 mmol) in DCM (20 mL), carbon tetrabromide (2.67 g, 10 mmol) and triphenyl phosphine (3.37 g, 10 mmol) were added and stirred the mixture at room temperature for 4 h. After completion, the reaction mixture was diluted with water (10 mL) and separated the layers. The aqueous layer was further extracted with DCM (2 ⁇ 20 mL) and the combined organic layer was dried and concentrated.
  • Step-1 To a stirred solution of 3-aminopyridine (3.0 g, 31.9 mmol) in THF (25 mL) at 0° C., acetic anhydride (3.70 g, 38 mmol) was added and stirred the mixture at room temperature for 8 h. After completion, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic layer was dried over sodium sulphate and concentrated to obtain N-(pyridin-3-yl)acetamide (Yield: 2.5 g, 58%) as white solid.
  • Step-1 A mixture of 1-bromo-3-fluoro-2-(trifluoromethyl)benzene (15 g, 62 mmol), phenyl boronic acid (22.7 g, 186 mmol), 2M sodium carbonate (150 mL), toluene (225 mL) and MeOH (75 mL) was degassed with nitrogen gas for 10 minutes. To this mixture, PdCl 2 (dppf)DCM complex (5.75 g, 8.21 mmol) was added and degassed for another 5 minutes with nitrogen. After sealing the vessel, the mixture was heated at 90° C. for 12 h. After completion, the reaction was diluted with water (300 mL) and extracted with EtOAc (3 ⁇ 300 mL).
  • Step-2 To a solution of 3-fluoro-2-(trifluoromethyl)-1,1′-biphenyl (17.0 g, 70.83 mmol) in DMSO (30 mL), KCN (4.6 g, 70.83 mmol) was added and stirred the mixture at 150° C. for 16 h. After completion, the reaction was diluted with water (100 mL) and extracted with EtOAc (3 ⁇ 100 mL). The organic layer was dried over sodium sulphate and concentrated.
  • Step-3 To a solution of 2-(trifluoromethyl)-[1,1′-biphenyl]-3-carbonitrile (1.0 g, 4.0 mmol) in dry DCM (5 mL) at ⁇ 65° C., DIBAl-H (1M solution in hexanes, 6.0 mL, 6.0 mmol) was added drop wise and stirred the mixture at ⁇ 65° C. for 1 h. After completion, the reaction was quenched with cold water (20 mL) and extracted with DCM (3 ⁇ 25 mL). The organic layer was dried over sodium sulphate and concentrated.
  • Step-4 To a solution of 2-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde (3.0 g, 12 mmol) in EtOH (30 mL) and THF (10 mL) at 0° C., sodium borohydride (0.90 g, 24 mmol) was added and allowed to stir at room temperature for 2 h. After completion of reaction, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 ⁇ 100 mL). The organic layer was dried over sodium sulphate and concentrated to obtain (2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methanol (Yield: 2.70 g, 90%) as yellow sticky liquid.
  • Step-5 To a solution of (2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methanol (0.1 g, 0.39 mmol) in DCM (10 mL) at 0° C., triphenyl phosphine (0.25 g, 0.99 mmol) and carbon tetrabromide (0.33 g, 0.99 mmol) were added and allowed the mixture to stir at room temperature for 8 h. After completion of reaction, the reaction was diluted with water (10 mL) and extracted with DCM (3 ⁇ 20 mL).
  • Step-1 To a stirred solution of dimethyl (1R,2S)-cyclopropane-1,2-dicarboxylate (2.0 g, 12.6 mmol) in THF (40 mL), a solution of lithium hydroxide monohydrate (0.53 g, 12.6 mmol) in water (40 mL) was added slowly and stirred for about 1 h. The reaction was cooled to 0° C. and pH was adjusted to 5-6.
  • Step-2 To a solution of (1S,2R)-2-(methoxycarbonyl)cyclopropane-1-carboxylic acid (0.80 g, 5.5 mmol) in THF (15 mL) under nitrogen atmosphere at 0° C., borane-DMS (0.84 g, 11.1 mmol) was added and allowed the reaction mixture to stir at room temperature for 6 h. After completion, the reaction was quenched with MeOH (10 mL) at 0° C. and concentrated under vacuum.
  • Step-3 To a stirred solution of methyl (1R,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate (0.25 g, 1.9 mmol) in DCM (5 mL), triethylamine (0.58 g, 5.7 mmol), and DMAP (23 mg, 0.19 mmol) were added and stirred for 10 minutes. To this mixture, tosyl chloride (0.55 g, 2.8 mmol) was added and allowed the mixture to stir at room temperature for 6 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 ⁇ 15 mL). The organic layer was dried over sodium sulphate and concentrated.
  • Prep-HPLC methods Compounds purified by prep Method Column Mobile phase HPLC A Xbridge Shield C-18, 19 ⁇ 5 Mm Ammonium 32, 12, 86 250 mm, 10 u Acetate in water: Acetonitrile B Xselect CSH phenyl 5 Mm Ammonium 46, 49, 85, hexyl, 19 ⁇ 250 mm, 5 u Acetate in water: 56, 93, 94 Acetonitrile C Xselect CSH phenyl 0.1% TFA in water: 47 hexyl, 19 ⁇ 250 mm, 5 u Acetonitrile D Sunfire C18, 19 ⁇ 250 5 mM Ammonium 76, 52, 81 mm, 10 ⁇ Acetate in water: Acetonitrile.
  • Step 1 To a solution of 4-hydroxy-2,3-dihydro-1H-inden-1-one (2.0 g, 13.5 mmol) in TFA (20 mL) at room temperature was added triethylsilane (5.3 mL, 33.72 mmol). The mixture was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was quenched with sodium bicarbonate solution, extracted into ethyl acetate.
  • Step 2 To a mixture of 2,3-dihydro-1H-inden-4-ol (1.8 g, 13.43 mmol) in DCM (20 mL) was added TiCl 4 (2.7 mL, 24.17 mmol) at 0° C. and the reaction mixture was stirred for 15 min. Dichloro(methoxy)methane (1.3 mL, 14.77 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with cold water and extracted with DCM.
  • Step 3 To a mixture of 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.31 g, 1.91 mmol, 1 equiv) in ACN (10 mL) was added potassium carbonate (0.39 g, 2.87 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 15 min. 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.5 g, 1.91 mmol, 1.0 equiv) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with DCM.
  • Step 4 To a mixture of 7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.1 g, 0.29 mmol) and (S)-piperidine-2-carboxylic acid (0.045 g, 0.35 mmol) in DMF:MeOH (10 mL) was added one drop of acetic acid at room temperature and the reaction mixture was stirred for 15 min. Sodium cyanoborohydride (0.054 g, 0.87 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM.
  • Step 2 To a solution of 5,7-dimethoxy-2,3-dihydro-1H-inden-1-one (3.5 g, 18.22 mmol) in DCM (50 mL) was added BBr 3 (1.71 mL, 17.18 mmol) drop wise over a period of 5 min at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water and extracted with DCM.
  • Step 3 To a mixture of sodium borohydride (2.24 g, 58.98 mmol) in THF (50 mL) was added BF 3 .Et 2 O (24.2 mL, 196.66 mmol) drop wise over a period of 10 min at 0° C. After stirring at 0° C. for 1 h, 7-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (3.5 g, 19.66 mmol) in THF (20 mL) was added to the reaction mixture which was further stirred at room temperature for 16 h. The reaction mixture was quenched with ice water, extracted with DCM.
  • Step 4 To a solution of 6-methoxy-2,3-dihydro-1H-inden-4-ol (2.5 g, 15.24 mmol) in DCM (50 mL) was added TiCl 4 (3.0 mL, 27.13 mmol) at 0° C. and stirred for 15 min. Dichloro(methoxy)methane (1.5 mL, 16.76 mmol) was added to the reaction mixture at 0° C. and stirred for additional 2 h at room temperature. The reaction mixture was quenched with cold water and extracted with DCM.
  • Step 5 To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.1 g, 0.52 mmol) in ACN (15 mL) was added potassium carbonate (0.10 g, 0.78 mmol) at room temperature. The mixture was stirred for 15 min and 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.13 g, 0.52 mmol) was added to the reaction mixture at room temperature. The reaction mixture was further stirred for 5 h. The reaction mixture was quenched with water and extracted with DCM.
  • Step 6 To a mixture of 5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.05 g, 0.13 mmol) and N-(2-aminoethyl)acetamide (0.02 g, 0.20 mmol) in DMF:MeOH (10 mL) was added one drop acetic acid at room temperature. The mixture was stirred for 15 min and sodium cyanoborohydride (0.025 g, 0.40 mmol) was added to the reaction mixture. The reaction mixture was further allowed to stir at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM.
  • Step 1 To a solution of 5-bromo indole (1 g, 5.1 mmol) in DMF (60 mL) was added NaH (0.22 g, 5.6 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min. Then 1-bromo-3-chloropropane (0.88 g, 5.6 mmol) was added to the reaction mixture at 0° C. and the reaction was stirred at room temperature for 6 h. The reaction mixture was quenched with water and extracted into ethyl acetate (2 ⁇ 100 mL).
  • Step 2 To a stirred solution of 4-bromo-1-(3-chloropropyl)-1H-indole (0.9 g, 3.3 mmol) and (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (0.98 g, 3.97 mmol) in dioxane:water (20 mL: 4 mL) were added Xphos (0.3 g, 0.33 mmol), CsF (1 g, 6.6 mmol), and Pd 2 (dba) 3 (0.27 g, 0.33 mmol) simultaneously and the reaction mixture was purged with nitrogen for 15 min. The reaction mixture was then heated at 85° C.
  • Step 3 To a solution of (3-(1-(3-chloropropyl)-1H-indol-4-yl)-2-methylphenyl)methanol (0.2 g, 0.6 mmol) in DMF (10 mL) were added 3,3-difluoropyrrolidine hydrochloride (0.133 g, 0.95 mmol), sodium iodide (0.143 g, 0.95 mmol) and K 2 CO 3 (0.172 g, 1.27 mmol) simultaneously and the reaction mixture was heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ice cooled water and extracted with ethyl acetate (2 ⁇ 50 mL).
  • Step 4 To a stirred solution (3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylphenyl)methanol (0.3 g, 0.78 mmol) in DCM (20 mL) was added PBr 3 (0.42 g, 1.56 mmol) drop wise at 0° C. and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (2 ⁇ 50 mL).
  • Step 5 To a stirred solution of 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.05 g, 0.13 mmol) and 4-(3-(bromomethyl)-2-methylphenyl)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indole (0.2, 0.34 mmol) in ACN (10 mL) was added K 2 CO 3 (0.07 g, 0.41 mmol) and the reaction mixture was stirred for 14 h at room temperature. The reaction mixture was quenched with water, extracted into ethyl acetate (2 ⁇ 50 mL).
  • Step 6 To a solution of 7-((3-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-4-yl)-2-methylbenzyl)oxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.05 g, 0.09 mmol) in MeOH (2 mL) and DMF (2 mL) were added (S)-piperidine-2-carboxylic acid (0.037 g, 0.28 mmol) and acetic acid (0.05 mL) simultaneously and the reaction mixture was stirred at 50° C. for 2 h.
  • reaction mixture was then cooled to 0° C., NaCNBH 3 (0.030 g, 0.283 mmol) was added and the reaction mixture was stirred at r.t for 16 h.
  • the reaction mixture was evaporated; the crude was taken in DCM (15 mL) and washed with water and brine.
  • Step-1 To a solution of o-cresol (4.0 g, 0.0369 mol) in acetonitrile (100 mL), magnesium chloride (5.2 g, 0.055 mol) and triethylamine (9.35 g, 0.092 mol) were added and the mixture was stirred for 15 minutes. Paraformaldehyde (5.5 g, 0.185 mol) was added and the mixture was heated at 90° C. for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was diluted with aqueous 1N HCl solution (100 mL).
  • Step-2 To a solution of 2-hydroxy-3-methylbenzaldehyde (10 g, 70 mmol) in acetic anhydride (15 g, 146 mmol), sodium acetate (15 g, 183 mmol) was added. The mixture was heated at 180° C. for 10 h. After completion of reaction, the mixture was cooled and diluted with water (300 mL). The mixture was extracted with EtOAc (3 ⁇ 500 mL) and the combined extracts were washed with saturated sodium bicarbonate solution (250 mL), water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure.
  • Step-3 To a solution of 8-methyl-2H-chromen-2-one (8.0 g, 50 mmol) in AcOH (60 mL), 10% palladium on carbon (50% wet, 4.0 g) was added under nitrogen and the resulting mixture was hydrogenated using a hydrogen balloon for 4 h at room temperature. After completion of reaction, the reaction mixture was filtered over celite bed and the bed was washed with EtOAc (20 mL). The filtrate was washed with saturated sodium bicarbonate solution (10 mL), water (10 mL), brine (10 mL), dried over sodium sulfate and concentrated under vacuum to obtain 8-methylchroman-2-one (3.40 g, crude).
  • Step-4 A mixture of 8-methylchroman-2-one (2.0 g, 13.5 mmol) and anhydrous AlCl 3 (5.4 g, 40.5 mmol) was heated at 180° C. for 2 h. After completion of the reaction, it was cooled and quenched with ice cold water (100 mL). The aqueous mixture was extracted with EtOAc (3 ⁇ 100 mL) and the EtOAc extract was dried over sodium sulfate and concentrated. The resulting residue was triturated with pentane and filtered to obtain 4-hydroxy-5-methyl-2,3-dihydro-1H-inden-1-one (Yield: 1.7 g, 67%) as brown solid.
  • Step-5 To a solution of 4-hydroxy-5-methyl-2,3-dihydro-1H-inden-1-one (0.70 g, 4.3 mmol) in 1,2-dichloroethane (20 mL) at room temperature under nitrogen atmosphere, sodium cyanoborohydride (0.8 g, 12.9 mmol) and ZnI 2 (5.5 g, 17 mmol) were added slowly and the resulting mixture was heated at 80° C. for 16 h. After completion, the reaction mixture was quenched with water (50 mL) and filtered through celite bed. The bed was washed with EtOAc (200 mL) and the filtrate was dried over sodium sulfate and concentrated under vacuum.
  • sodium cyanoborohydride 0.8 g, 12.9 mmol
  • ZnI 2 5.5 g, 17 mmol
  • Step-6 To a solution of 5-methyl-2,3-dihydro-1H-inden-4-ol (0.50 g, 3.3 mmol) in TFA (12.5 mL), hexamine (0.56 g, 4.0 mmol) was added and the mixture was stirred at 120° C. for 3 h. After cooling the mixture to 0° C., a 10% aqueous H 2 SO 4 solution (12.5 mL) was added and the mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and quenched with solid sodium bicarbonate until the effervescence stopped.
  • Step-7 To a solution of 7-hydroxy-6-methyl-2,3-dihydro-1H-indene-4-carbaldehyde (0.22 g, 1.25 mmol) in acetonitrile (5 mL), potassium carbonate (0.25 g, 1.86 mmol) was added and the reaction mixture was stirred for 30 min. 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.32 g, 1.25 mmol) was added and the reaction mixture was stirred for 5 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 ⁇ 10 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-8 A solution of 6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (100 mg, 0.28 mmol), (S)-piperidine-2-carboxylic acid (50 mg, 0.42 mmol) and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (50 mg, 0.84 mmol) was added and the mixture was stirred for 16 h. After completion, the reaction mixture was concentrated and the residue was diluted with water (10 mL).
  • Step-1 To a solution of 4-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g, 33.7 mmol) in 1,2-dichloroethane (500 mL) at room temperature under nitrogen atmosphere, sodium cyanoborohydride (8.48 g, 135 mmol) and ZnI 2 (43 g, 135 mmol) were added slowly and the resulting mixture was heated at 80° C. for 5 h. After completion of reaction, the reaction mixture was filtered through silica gel bed in warm condition and washed with warm DCM (500 mL).
  • Step-2 To a solution of 2,3-dihydro-1H-inden-4-ol (3.3 g, 24.6 mmol) in chloroform (150 mL) at 60° C., N-chlorosuccinimide (3.2 g, 24.6 mmol) was added. After stirring at room temperature for 1 h, conc.HCl (1 mL) was added and the mixture was refluxed for 10 h. After completion, the reaction mixture was cooled and diluted with water (100 mL). The aqueous mixture was extracted with DCM (2 ⁇ 100 mL) and the combined organic layer was dried over sodium sulfate and concentrated.
  • Step-3 To a solution of 5-chloro-2,3-dihydro-1H-inden-4-ol (1.3 g, 7.7 mmol) in TFA (50 mL), hexamine (940 mg, 9.25 mmol) was added and the mixture was heated at 120° C. for 2 h. After completion, the reaction mixture was quenched with solid sodium bicarbonate (5 g). After diluting with water (30 mL), the mixture was extracted with EtOAc (2 ⁇ 50 mL) and the organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-4 To a solution of 6-chloro-7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.60 g, 3.06 mmol) in acetonitrile (10 mL), potassium carbonate (0.63 g, 4.6 mmol) was added and the reaction mixture was stirred for 30 minutes. To this mixture, 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.79 g, 3.06 mmol) was added and was continued for 16 h. After completion of reaction, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 ⁇ 10 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-5 A solution of 6-methyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (120 mg, 0.30 mmol), (S)-piperidine-2-carboxylic acid (60 mg, 0.40 mmol) and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (54 mg, 0.90 mmol) was added and the reaction mixture was stirred further for 16 h.
  • reaction mixture was concentrated and the residue was diluted with water (10 mL) and saturated sodium bicarbonate solution (2 mL). The aqueous mixture was extracted with EtOAc (3 ⁇ 10 mL). The combined organic layer was dried over sodium sulphate and concentrated.
  • Step-1 To a solution of 4-hydroxy-2,3-dihydro-1H-indene-5-carbaldehyde (0.50 g, 3.08 mmol) in acetonitrile (20 mL), potassium carbonate (0.64 g, 4.6 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature. After stirring, 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.79 g, 3.08 mmol) was added and the reaction mixture was allowed to stir at room temperature for 6 h. After completion of reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 ⁇ 25 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 To a solution of 4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carbaldehyde (0.80 g, 2.3 mmol) in acetonitrile (30 mL) and water (2 mL) at 0° C., NaH 2 PO 4 (112 mg, 0.9 mmol), 30% hydrogen peroxide solution (4 mL) and sodium chlorite (0.63 g, 7.0 mmol) were added successively. After stirring at 0° C. for 3 h, the reaction mixture was diluted with water (50 mL) and extracted with DCM (3 ⁇ 50 mL).
  • Step-3 To a solution of 4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylic acid (0.30 g, 0.837 mmol) in acetone (10 mL), potassium carbonate (0.29 g, 2.09 mmol) and methyl iodide (0.18 g, 1.26 mmol) were added. The reaction mixture was heated to reflux for 4 h. After completion of the reaction, the reaction mixture was cooled and filtered.
  • Step-4 To a solution of methyl 4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate (0.20 g, 0.537 mmol) in TFA (5 mL), hexamine (0.112 g, 0.805 mmol) was added. The mixture was stirred at 120° C. for 3 h. After cooling the mixture to 0° C., a 10% aqueous H 2 SO 4 solution (5 mL) was added and heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and quenched with solid sodium bicarbonate until the effervescence stopped.
  • Step-5 To a solution of methyl 7-formyl-4-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (0.12 g, 0.54 mmol) in acetonitrile (5 mL), potassium carbonate (0.11 g, 0.82 mmol) was added. The reaction mixture was stirred for 30 minutes. To this mixture, 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.14 g, 0.54 mmol) was added. The reaction mixture was stirred for 6 h. After completion of reaction, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 ⁇ 25 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-6 A solution of methyl 7-formyl-4-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-5-carboxylate (70 mg, 0.175 mmol), N-(2-aminoethyl)acetamide (30 mg, 0.26 mmol) and acetic acid (1 drop) in DMF (2.5 mL) and MeOH (2.5 mL) was stirred at room temperature for 8 h. To this reaction mixture, sodium cyanoborohydride (33 mg, 0.525 mmol) was added and the reaction mixture was stirred further for 8 h.
  • Step-1 To a solution of 3-bromo-2-methylphenol (9.8 g, 52 mmol) in DMF (80 mL), 1,3-dichloropropane (11.73 g, 10 mmol) and potassium carbonate (21.5 g, 156 mmol) were added. The reaction mixture was stirred at 80° C. for 12 h under nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc (100 mL), washed with ice cold water (50 mL) and brine (30 mL). The organic phase was dried over sodium sulphate and concentrated under vacuum to give a crude product.
  • Step-2 To a stirred solution of 1-bromo-3-(3-chloropropoxy)-2-methylbenzene (10.1 g, 38 mmol) in DMF (60 mL), 3,3-difluoropyrrolidine (11 g, 76 mmol), potassium carbonate (22.5 g, 163 mmol) and sodium iodide (8.5 g, 57 mmol) were added and the reaction mixture was heated at 80° C. for 12 h under nitrogen atmosphere.
  • Step-3 To a solution of 1-(3-(3-bromo-2-methylphenoxy)propyl)-3,3-difluoropyrrolidine (2 g, 0.059 mol) and (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (1.78 g, 71 mmol) in toluene:ethanol:water (1:1:1) (30 mL) at room temperature, potassium carbonate (2.47 g, 17 mmol) was added and the reaction mixture was purged with nitrogen for 15 minutes.
  • Step-4 To a stirred solution of (3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (0.55 g, 14 mmol) and 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.28 g, 14 mmol) in dry THF (20 mL) under nitrogen atmosphere at 0° C., triphenylphosphine (0.96 g, 35 mmol), and DEAD (1.15 g, 66 mmol) were added and the reaction mixture was stirred at room temperature for 24 h.
  • Step-5 A solution of 7-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (100 mg, 0.185 mmol), (S)-piperidine-2-carboxylic acid (36 mg, 0.27 mmol) and acetic acid (1 drop) in DMF (2 mL) and MeOH (2 mL) was stirred at room temperature for 2 h.
  • Step-1 A mixture of 7-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (20 g, 0.1122 mol) in DCE (200 mL), zinc iodide (107.48 g, 0.337 mol) and sodium cyanoborohydride (28.21 g, 0.448 mol) were heated at 75° C. for 8 h. The reaction mixture was filtered and the residue was washed with DCM (200 mL). The filtrate was washed with water (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate and concentrated under vacuum.
  • Step-3 To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (600 mg, 3.12 mmol) in DCM (100 mL) at 0° C., 1M BBr 3 solution in DCM (4.7 mL, 4.68 mmol) was added slowly and the solution was allowed to stir at room temperature for 6 h. After completion, the reaction mixture was quenched with water (100 mL) and extracted with DCM (2 ⁇ 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-4 To a solution of 5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.40 g, 2.247 mmol) in acetonitrile (20 mL), potassium carbonate (0.37 g, 2.69 mmol) and 3-(bromomethyl)-2-methyl-1,1′-biphenyl (0.59 g, 2.25 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 20 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-5 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.50 g, 1.39 mmol) in acetonitrile (20 mL), potassium carbonate (0.35 g, 2.5 mmol) and 3-(chloromethyl)benzonitrile (0.41 g, 2.0 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-6 A solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (100 mg, 0.21 mmol), (S)-piperidine-2-carboxylic acid (40.8 mg, 0.32 mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2 drops) in DMF (5 mL) was stirred at 70° C. for 4 h. After completion, the reaction mixture was poured on to ice-cold water (10 mL). The solid was filtered and dissolved in DCM.
  • Step-1 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.40 g, 1.117 mmol) in DMF (20 mL), potassium carbonate (0.46 g, 3.38 mmol) and 3-(chloromethyl)-5-fluoropyridine (0.325 g, 2.25 mmol) was added and stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 To a solution of 5-((5-fluoropyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (50 mg, 0.11 mmol), (S)-piperidine-2-carboxylic acid (52 mg, 0.32 mmol) in MeOH (3 mL) and DMF (3 mL), sodium cyanoborohydride (19 mg, 0.32 mmol) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 8 h.
  • Step-1 To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (1.0 g, 3.6 mmol) in 1,4-dioxane (10 mL) at 0° C., 4M HCl in 1,4-dioxane (15 mL) was added drop wise and allowed the mixture to stir at room temperature for 3 h. After completion, the reaction mixture was concentrated under vacuum to obtain (S)-5-azaspiro[2.4]heptane-6-carboxylic acid hydrochloride (700 mg, crude) as off-white solid.
  • Step-2 A solution of 5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (200 mg, 0.42 mmol), (S)-5-azaspiro[2.4]heptane-6-carboxylic acid hydrochloride (89 mg, 0.50 mmol) and acetic acid (2 drops) in MeOH (2.5 mL) and DMF (2.5 mL) was stirred at room temperature for 30 minutes. To this mixture, sodium cyanoborohydride (39 mg, 0.63 mmol) was added and continued stirring at room temperature for 16 h.
  • Step-1 To a solution of trifluoroethanol (500 mg, 5.0 mmol) in DCM (10 mL), triethylamine (1.5 g, 15 mmol) was added and cooled to 0° C. To this mixture, p-toluene sulfonyl chloride (1.2 g, 6.0 mmol) was added and allowed the reaction mixture to stir at room temperature for 6 h. After completion, the reaction mixture was diluted with water (10 mL) and separated the layers. The aqueous layer was further extracted with EtOAc (2 ⁇ 10 mL) and the combined organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-2 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.40 g, 1.12 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (0.34 g, 1.34 mmol) in DMF (8 mL), potassium carbonate (0.28 g, 2.0 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 25 mL). The organic layer was dried over sodium sulfate and concentrated.
  • Step-3 A solution of 7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (100 mg, 0.23 mmol), (S)-piperidine-2-carboxylic acid (87 mg, 0.68 mmol), sodium cyanoborohydride (42.2 mg, 0.68 mmol) and acetic acid (2 drops) in MeOH (2 mL) and DMF (3 mL) was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with 10% MeOH in DCM (3 ⁇ 25 mL).
  • Step-5 To a solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (135 mg, 0.29 mmol), N-(2-aminoethyl)-N-methylacetamide (100 mg, 0.86 mmol) in 1:1 mixture of MeOH and DMF (5 mL), acetic acid (2 drops) was added and stirred for 15 minutes. To this mixture, sodium cyanoborohydride (53 mg, 0.86 mmol) was added and continued stirring the reaction mixture at room temperature for 16 h.
  • Step-1 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.250 g, 0.68 mmol) in DMF (10 mL), potassium carbonate (0.192 g, 1.39 mmol) and 3-(1-bromoethyl)benzonitrile (0.22 g, 1.04 mmol) were added and stirred the reaction mixture at room temperature for 10 minutes. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 A solution of 3-(1-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)ethyl)benzonitrile (150 mg, 0.31 mmol), N N-(2-aminoethyl)acetamide (47 mg, 0.46 mmol) in 1:1 mixture of MeOH and DMF (5 mL), acetic acid (5 drops) was added and stirred for 15 minutes. To this mixture, sodium cyanoborohydride (38 mg, 0.62 mmol) was added and continued stirring the reaction mixture at room temperature for 16 h.
  • Step-1 A solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (150 mg, 0.40 mmol), N-(piperidin-3-yl)acetamide (170 mg, 1.20 mmol) in triethylamine (82 mg) and acetic acid (5 drops) was stirred for 1 h. To this mixture, sodium cyanoborohydride (74.6 mg, 1.20 mmol) was added and continued stirring the reaction mixture at room temperature for 16 h.
  • Step-1 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.20 g, 0.55 mmol) in acetonitrile (20 mL), potassium carbonate (0.30 g, 2.23 mmol) and 5-(chloromethyl)nicotinonitrile (5, 0.25 g, 1.67 mmol) was added and stirred the reaction mixture at RT for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-6 A solution of 5-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (100 mg, 0.21 mmol), (S)-piperidine-2-carboxylic acid (40.8 mg, 0.32 mmol), sodium cyanoborohydride (66.4 mg, 1.06 mmol) and acetic acid (2 drops) in DMF (5 mL), the reaction mixture was stirred at 70° C. for 4 h. After completion, the reaction mixture was poured on ice cold water (10 mL) and collected the white solid by filtration.
  • Step-1 To a stirred solution of N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (1, 0.3 g, 0.523 mmol) in DMF (8 mL), formaldehyde (64.4 mg, 2.14 mmol) and formic acid (98 mg, 2.14 mmol) were added and stirred for 15 minutes. To this mixture, sodium cyanoborohydride (133 mg, 2.14 mmol) was added and stirred the reaction mixture for 4 h at room temperature.
  • Step-1 Preparation of 4-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile
  • Step-2 N-(2-(((5-((4-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide
  • Step-1 To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (918 mg, 4.7 mmol) and 3-(hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile (1.0 g, 4.7 mmol) in dry THF (30 mL), triphenyl phosphine (3 g, 0.035 mol) was added and cooled the mixture to 0° C. To this mixture, DEAD (266 mg, 0.014 mol) and stirred the mixture for 2 h. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 ⁇ 100 mL).
  • Step-2 To a solution of 3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile (60 mg, 0.156 mmol) and (S)-piperidine-2-carboxylic acid (26 mg, 0.20 mmol) in DMF (3 mL), acetic acid (3 drops) was added and stirred the reaction mixture for 10 minutes. To this mixture, sodium cyanoborohydride (29 mg, 0.47 mmol) was added and stirred at 70° C. for 3 h. After completion, the reaction mixture was diluted with ice cold water (10 mL) and collected the resulting solid by filtration.
  • Step-1 To a solution of 3-(((7-formyl-6-methoxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile (250 mg, 0.65 mmol), N 1 ,N 2 -dimethylethane-1,2-diamine (115 mg, 1.30 mmol), and acetic acid (2 drops) in DMF (3 mL)) and MeOH (3 mL), the reaction mixture was stirred at rt for 30 minutes. To this mixture, sodium cyanoborohydride (40 mg, 0.130 mmol) was added and stirred for 16 h.
  • Step-2 To a stirred solution of 3-(((6-methoxy-7-((methyl(2-(methylamino)ethyl)amino)methyl)-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile (80 mg, 0.176 mmol), AcOH (5 drops) in DMF (5 mL), HOBt (35 mg, 0.26 mmol), EDC.HCl (50 mg, 0.26 mmol), N,N-diisopropylethylamine (68 mg, 0.53 mmol) were added and stirred the mixture for 12 h at room temperature.
  • Step-1 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.40 g, 1.12 mmol) in DMF (10 mL), potassium carbonate (0.46 g, 3.38 mmol) and methyl 5-bromopentanoate (0.217 g, 1.22 mmol) was added and the reaction mixture was stirred at 60° C. for 6 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 To a solution of methyl 5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (150 mg, 0.32 mmol), in MeOH (3 mL) and DMF (3 mL), N-(2-aminoethyl)acetamide (32.7 mg, 0.48 mmol) and acetic acid (3 drops) were added and stirred the reaction mixture for 10 minutes. To this mixture, sodium cyanoborohydride (57 mg, 0.935 mmol) was added and the mixture was stirred at room temperature for 16 h.
  • Step-3 To a stirred solution of methyl 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (70 mg, 0.125 mmol) in THF (3 mL) and water (1.5 mL), lithium hydroxide (10.5 mg, 0.25 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (5 mL) and acidified with 1N HCl.
  • Step-1 To a stirred solution of methyl 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (60 mg, 0.107 mmol) in MeOH (10 mL) at ⁇ 60° C. in a steel bomb, ammonia gas was purged for 10 minutes, after sealing the steel bomb the mixture was heated at 60° C. and stirred for 16 h. After completion, excess ammonia was removed by flushing nitrogen gas and concentrated the reaction mixture.
  • Step-1 To a solution of methyl 5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (340 mg, 0.71 mmol), in MeOH (4 mL) and DMF (4 mL), (S)-piperidine-2-carboxylic acid (102 mg, 0.79 mmol) and acetic acid (3 drops) were added and stirred for 2 h. To this mixture, sodium cyanoborohydride (134 mg, 2.1 mmol) was added and the mixture was stirred at room temperature for 16 h.
  • Step-2 To a stirred solution of (S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (70 mg, 0.11 mmol) in THF (3 mL) and water (1.5 mL), lithium hydroxide (10.5 mg, 0.23 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and acidified with 1N HCl.
  • Step-1 To a stirred solution of (S)-1-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (103 mg, 0.18 mmol) in MeOH (10 mL) at ⁇ 35° C. in a steel bomb, ammonia gas was purged for 5 minutes. After sealing the steel bomb, the mixture was heated at 55° C. and stirred for 36 h. After completion, excess ammonia was removed by flushing nitrogen gas and concentrated the reaction mixture.
  • Step-1 To a solution of 5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.34 g, 1.92 mmol) in acetonitrile (20 mL), potassium carbonate (0.31 g, 2.30 mmol) and 3-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (0.50 g, 1.92 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 20 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 To a solution of 3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile (0.75 g, 2.03 mmol) in DMF (15 mL), potassium carbonate (0.82 g, 6.09 mmol) and 5-(chloromethyl)nicotinonitrile (0.92 g, 6.09 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-3 To a solution of 5-(((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinonitrile (180 mg, 0.37 mmol), (S)-piperidine-2-carboxylic acid (40 mg, 0.33 mmol) in DMF (2 mL) and MeOH (2 mL), acetic acid (2 drops) was added and stirred the mixture for 2 h. To this mixture, sodium cyanoborohydride (68 mg, 1.11 mmol) and) was added and continued stirring at room temperature for 16 h.
  • Step-1 To a solution of methyl 4-(((5-((3-cyanobenzyl)oxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino) bicyclo[2.2.2]octane-1-carboxylate (160 mg, 0.24 mmol) in THF (6 mL) and water (4 mL), lithium hydroxide (83 mg, 1.99 mmol) was added and stirred the mixture at room temperature for 12 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL).
  • Step-1 To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.50 g, 1.5 mmol) and 3-(bromomethyl)-2-(trifluoromethyl)-1,1′-biphenyl (0.29 g, 1.5 mmol) in ACN (10 mL), potassium carbonate (0.31 g, 2.25 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 40 mL). The organic layer was dried over sodium sulphate and concentrated.
  • Step-2 To a stirred solution of 5-methoxy-7-((2-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.10 g, 0.23 mmol), (S)-piperidine-2-carboxylic acid (27 mg, 0.21 mmol) in DMF (1 mL) and MeOH (1 mL), acetic acid (2 drops) was added and continued stirring of the mixture for 1 h. To this mixture, sodium cyanoborohydride (40 mg, 0.69 mmol) and) was added and continued stirring at room temperature for 16 h and the mixture was heated at 50° C. for 5 h.
  • Step-1 To a stirred solution of 1-methyl-3-hydroxymethylpiperidine (2 g, 15.5 mmol) in DCM (30 mL) at 0° C., triethylamine (4.9 g, 46 mmol) and tosyl chloride (4.41 g, 23.2 mmol) were added and allowed the mixture to stir at room temperature for 6 h. After completion, the reaction mixture was diluted with water (30 mL) and extracted with DCM (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (200 mg, 0.558 mmol) in DMF (5 mL), potassium carbonate (231 mg, 1.67 mmol) and (1-methylpiperidin-3-yl)methyl 4-methylbenzenesulfonate (238 mg, 0.84 mmol) were added and stirred the reaction mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with ice cold water (15 mL) and extracted with 5% MeOH in DCM (3 ⁇ 20 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-3 A solution of 7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-5-((1-methylpiperidin-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (150 mg, 0.319 mmol), (S)-piperidine-2-carboxylic acid (123 mg, 0.96 mmol) in DMF (2.5 mL) and MeOH (2.5 mL), acetic acid (3 drops) were added and stirred the mixture for 1 h. To this mixture, sodium cyanoborohydride (60 mg, 0.96 mmol) and) was added and continued stirring at room temperature for 16 h.
  • Step-1 To a solution of 3-(((7-formyl-6-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)methyl)-[1,1′-biphenyl]-2-carbonitrile (0.25 g, 0.697 mmol) in ACN (10 mL), potassium carbonate (0.280 g, 2.03 mmol) and methyl 5-bromopentanoate (0.396 g, 2.03 mmol) were added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 A solution of methyl 5-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)pentanoate (220 mg, 0.46 mmol), (S)-piperidine-2-carboxylic acid (176 mg, 1.366 mmol) in DMF (2 mL) and MeOH (2 mL), acetic acid (6 drops) was stirred for 30 minutes. To this mixture, sodium cyanoborohydride (86 mg, 1.366 mmol) and) were added and continued stirring at room temperature for 16 h.
  • Step-3 To a stirred solution of (S)-1-((7-((2-cyano-[1,1′-biphenyl]-3-yl)methoxy)-5-((5-methoxy-5-oxopentyl)oxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (70 mg, 0.117 mmol) in THF (3 mL) and water (1.5 mL), lithium hydroxide (9.8 mg, 0.23 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and acidified with 1N HCl.
  • Step-1 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.50 g, 1.39 mmol) in DMF (10 mL), potassium carbonate (0.288 g, 2.08 mmol) and 5-bromopentanenitrile (0.25 g, 1.53 mmol) were added and stirred the mixture at room temperature for 5 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-2 To a solution of 5-((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)pentanenitrile (150 mg, 0.35 mmol) in DMF (10 mL), N-(2-aminoethyl)acetamide (45 mg, 0.44 mmol) and acetic acid (2 drops) were added and stirred the mixture for 10 minutes. To this mixture, sodium cyanoborohydride (32 mg, 0.52 mmol) was added and the mixture was stirred at room temperature for 6 h.
  • Step-1 To a solution of 5-hydroxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (0.20 g, 0.55 mmol) in DMF (4 mL), potassium carbonate (0.227 g, 1.6 mmol) and methyl (1R,2S)-2-((tosyloxy)methyl)cyclopropane-1-carboxylate (0.321 g, 1.39 mmol) was added and stirred the mixture at room temperature for 12 h. After completion, the reaction mixture was diluted with water (6 mL) and extracted with EtOAc (3 ⁇ 10 mL).
  • Step-2 To a solution of methyl (1R,2S)-2-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopropane-1-carboxylate (150 mg, 0.32 mmol) in DMF (2 mL) and MeOH (2 mL), (S)-piperidine-2-carboxylic acid (61 mg, 0.48 mmol) and acetic acid (2 drops) were added and stirred the mixture for 30 minutes. To this mixture, sodium cyanoborohydride (60 mg, 0.95 mmol) was added and the mixture was stirred at 60° C.
  • Step-3 To a stirred solution of (S)-1-((5-(((1S,2R)-2-(methoxycarbonyl)cyclopropyl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (100 mg, 0.17 mmol) in THF (3 mL) and water (1.5 mL), lithium hydroxide (14 mg, 0.35 mmol) was added and stirred the mixture at room temperature for 6 h. After completion, the reaction mixture was diluted with water (5 mL) and acidified with 1N HCl (pH 5-6).
  • the aqueous mixture was extracted with 10% MeOH in DCM (3 ⁇ 10 mL) and combined organic extract was dried over sodium sulphate and concentrated.
  • the crude was purified by column chromatography (silica gel, 100-200 mesh) using 0-30% MeOH in DCM as eluent.
  • Step-1 A mixture of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (5 g, 0.023 mol), (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (8.6 g, 0.034 mol), potassium carbonate (9.5 g. 0.069 mol), toluene (50 mL), water (50 mL) and EtOH (50 mL) was degassed with nitrogen gas for 15 minutes. To this mixture, PdCl 2 (dppf)DCM (0.93 g, 1.15 mmol) was added and degassed for another 5 minutes with nitrogen.
  • Step-2 To a solution of 7-hydroxy-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (500 mg, 2.6 mmol) and (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (866 mg, 3.3 mmol) in dry THF (15 mL) at 0° C., triphenyl phosphine (1.7 g, 6.5 mmol) was added and stirred the mixture for 10 minutes at 0° C. To this mixture, DEAD (1.355 g, 7.8 mmol) was added and stirred the mixture for 30 minutes.
  • triphenyl phosphine 1.7 g, 6.5 mmol
  • Step-3 To a solution of 7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-indene-4-carbaldehyde (100 mg, 0.23 mmol) and (S)-piperidine-2-carboxylic acid (36 mg, 0.27 mmol) in DMF (3 mL), acetic acid (3 drops) was added and stirred for 10 minutes. To this mixture, sodium cyanoborohydride (43 mg, 0.69 mmol) was added and stirred the mixture at 80° C. for 3 h.
  • reaction mixture was diluted with ice cold water (10 mL) and extracted with 10% MeOH in DCM (3 ⁇ The solid was further dissolved in DCM (30 mL) and dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent.
  • the product was further purified by reverse phase prep-HPLC using Method-B to obtain (S)-1-((7-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-5-methoxy-2,3-dihydro-1H-inden-4-yl)methyl)piperidine-2-carboxylic acid (Yield: 35 mg, 28%) as white solid.
  • Step-1 A mixture of (3-bromo-2-methylphenyl)methanol (2 g, 9.95 mmol), o-tolylboronic acid (4.06 g, 29.84 mmol), sodium carbonate (12.4 g. 0.117 mol), toluene (27 mL), water (9 mL) and MeOH (9 mL) was degassed with nitrogen gas for 15 minutes. To this mixture, Pd(PPh 3 ) 4 (1.1 g, 0.99 mmol) was added and degassed for another 5 minutes with nitrogen. After sealing the vessel, the mixture was heated at 90° C. for 16 h. After completion, the reaction was diluted with water (50 mL) and extracted with EtOAc (3 ⁇ 50 mL).
  • Step-2 To a solution of (2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methanol (1.7 g, 8.01 mmol) in DCM (5 mL) at 0° C., PBr 3 (2.38 g, 8.8 mmol) was added and stirred the mixture at room temperature for 16 h. After completion, the reaction mixture was concentrated under vacuum and the crude was purified by flash chromatography (silica gel, 12 g cartridge) using 0-10% EtOAc in hexane as eluent to obtain 3-(bromomethyl)-2,2′-dimethyl-1,1′-biphenyl (Yield: 1.7 g, 77%) as colourless sticky liquid.
  • Step-3 To a solution of 5,7-dihydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.31 g, 1.7 mmol) in acetonitrile (10 mL), potassium carbonate (0.28 g, 2.01 mmol) and 3-(bromomethyl)-2,2′-dimethyl-1,1′-biphenyl (0.47 g, 1.7 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 20 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-4 To a solution of 7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (0.56 g, 1.5 mmol) in DMF (10 mL), potassium carbonate (0.416 g, 3.0 mmol) and 3-(chloromethyl)benzonitrile (0.29 g, 1.5 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 ⁇ 20 mL). The combined organic layer was dried over sodium sulfate and concentrated.
  • Step-5 To a solution of 3-(((7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-formyl-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (150 mg, 0.30 mmol) in DMF (4 mL) and MeOH (4 mL), N-(2-aminoethyl)acetamide (31 mg, 0.30 mmol) and acetic acid (2 drops) were added and stirred the mixture for 10 minutes. To this mixture, sodium cyanoborohydride (56 mg, 0.90 mmol) was added and the mixture was stirred at room temperature for 16 h.
  • the resulting product was further purified by reverse phase HPLC using method-A to obtain N-(2-(((5-((3-cyanobenzyl)oxy)-7-((2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (Yield: 100 mg, 21%) as white solid.
  • Step-1 To a solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (60 mg, 0.126 mmol) in MeOH (2 mL), THF (2 mL) at 0° C., sodium borohydride (12 mg, 0.40 mmol) was added slowly and allowed the mixture to stir at RT for 3 h. After completion, the reaction was quenched with water (10 mL) and extracted with DCM (2 ⁇ 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-2 To a solution of 3-(((4-(hydroxymethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl) methoxy)-2,3-dihydro-1H-inden-5-yl) oxy) methyl) benzonitrile (250 mg, 0.526 mmol) and pthalimide (229 mg, 1.31 mmol) in dry THF (5 mL), triphenyl phosphine (345 mg, 1.31 mmol) was added and cooled the mixture to 0° C. To this mixture, DIAD (266 mg, 1.31 mmol) was added and allowed the mixture to stir at room temperature for 6 h.
  • Step-3 To a solution of 3-(((4-((1,3-dioxoisoindolin-2-yl)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (300 mg, 0.495 mmol) in EtOH (15 mL), at room temperature, hydrazine hydrate solution (2 mL) was added slowly and allowed to stir the mixture at RT for 3 h. After completion, the reaction was quenched with water (10 mL) and extracted with DCM (2 ⁇ 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-1 A solution of 3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (40 mg, 0.084 mmol), triethylamine (12.7 mg, 0.21 mmol) in DCM (5 mL) was cooled to 0° C. To this mixture, acetyl chloride (16 mg, 0.021 mmol) was added and the reaction mixture was stirred at room temperature for 6 h.
  • Step-1 A solution of 3-(((4-(aminomethyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (150 mg, 0.31 mmol), 6-acetamidohexanoic acid (82 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), EDC.HCl (90 mg, 0.47 mmol) and DIPEA (244 mg, 1.89 mmol) in DMF (10 mL) was stirred for 12 h at room temperature.
  • reaction mixture was diluted with ice cold water (20 mL) and extracted with 10% MeOH in DCM (2 ⁇ 50 mL). The combined organic layer was washed with brine solution (20 mL), dried over sodium sulfate and concentrated.
  • Step-1 A solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (120 mg, 0.25 mmol), dimethylamine solution in methanol (4 mL), and acetic acid (1 drop) in DMF (4 mL) was stirred at room temperature for 2 h. To this mixture, sodium cyanoborohydride (47 mg, 0.76 mmol) was added and stirred for 12 h. After completion, the reaction mixture was poured on ice cold water (10 mL) and collected the white solid by filtration.
  • the aqueous layer was acidified to pH 4 using 6N HCl solution and then the mixture was extracted with 10% MeOH in DCM (2 ⁇ 100 mL). The combined organic layer was dried over sodium sulfate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent.
  • the compound was further purified by reverse phase HPLC using method-B to obtain 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinic acid (Yield: 20 mg, 16%) as white solid.
  • Step-1 To a solution of N-(2-(((5-((5-cyanopyridin-3-yl)methoxy)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)methyl)amino)ethyl)acetamide (1, 0.15 g, 0.25 mmol) in Ethanol (8 mL) and water (8 mL), potassium hydroxide (60 mg, 1.07 mmol) was added and refluxed for 6 h. After completion, the reaction mixture was diluted with water (20 mL) and washed with EtOAc (30 mL).
  • the aqueous layer was acidified to pH 4 using 6N HCl solution and the reaction mixture was extracted with 10% MeOH in DCM (2 ⁇ 100 mL). The combined organic layer was dried over sodium sulfate and concentrated. The resulting crude was purified by flash chromatography (silica gel, 4 g cartridge) using 0-10% MeOH in DCM as eluent.
  • the compound was further purified by reverse phase HPLC using method-B to obtain 5-(((4-(((2-acetamidoethyl)amino)methyl)-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)nicotinamide (Yield: 30 mg, 20%) as white solid.
  • Step-1 To a solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzonitrile (0.30 g, 0.63 mmol) in ethanol (10 mL) and water (10 mL), potassium hydroxide (0.15 g, 2.67 mmol) was added and refluxed for 12 h. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The aqueous layer was acidified to pH 4 using 6N HCl solution and the reaction mixture was extracted with 10% MeOH in DCM (2 ⁇ 100 mL).
  • Step-2 A solution of 3-(((4-formyl-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-inden-5-yl)oxy)methyl)benzamide (240 mg, 0.487 mmol), N-(2-aminoethyl)acetamide (50 mg, 0.487 mmol) and acetic acid (1 drop) in DMF (4 mL) and MeOH (4 mL) was stirred at room temperature for 2 h. To this mixture, sodium cyanoborohydride (92 mg, 1.46 mmol) was added and the reaction mixture was stirred for 16 h.
  • Step-1 To a solution of cyclopentanone (40 g, 476.19 mmol) and malononitrile (30 mL, 476.19 mmol) in MeOH (100 mL) and DMF (30 mL), CS 2 (100 mL, 1664.2 mmol) was added and stirred for 5 minutes. To this mixture, triethylamine (35 mL, 237.7 mmol) was slowly added drop wise and stirred the mixture at room temperature for 48 h.
  • Step-2 A solution of 3-hydroxy-1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitrile (13 g, 67.56 mmol) in 1N NaOH (250 mL) was stirred at 150° C. for 8 h. After completion, the reaction mixture was acidified with aqueous 6N HCl solution and filtered the solid. The solid was washed with cold water (20 mL) and dried under vacuum to obtain 1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (Yield: 6.2 g, crude) as red solid.
  • Step-3 To a solution of 1-mercapto-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (4.0 g, 23.95 mmol) in EtOH (100 mL), potassium carbonate (5.0 g, 36.17 mmol) and MeI (3.39 g, 2.39 mmol) were added and stirred the mixture at room temperature for 6 h. After completion, the reaction was quenched with water (100 mL) and extracted with DCM (2 ⁇ 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-4 To a solution of 1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridin-3-ol (3.0 g, 16.55 mmol) in benzene (50 mL), Ag 2 O (2.18 g, 9.40 mmol) and MeI (2.58 g, 18.23 mmol) were added and stirred the mixture at 80° C. for 16 h. After completion, the reaction was quenched with water (100 mL) and extracted with EtOAc (2 ⁇ 100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated.
  • Step-5 To a solution of 3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine (2.3 g, 11.73 mmol) in DCM (30 mL), Br 2 (2.0 g, 11.73 mmol) was added slowly and stirred at room temperature for 4 h. After completion, the reaction was concentrated under vacuum to obtain 4-bromo-3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine (Yield: 2.0 g, 62%) as off-white solid.
  • Step-6 To a solution of 4-bromo-3-methoxy-1-(methylthio)-6,7-dihydro-5H-cyclopenta[c]pyridine (2.0 g, 10.24 mmol) in DCM (50 mL) at 0° C., mCPBA (4.0 g, 25.60 mmol) was added and stirred the mixture at room temperature for 12 h. After completion, the reaction was quenched with aqueous saturated NaHCO 3 solution (100 mL) and extracted with DCM (2 ⁇ 70 mL).
  • Step-7 To a solution of (2-methyl-[1,1′-biphenyl]-3-yl)methanol (0.92 g, 4.64 mmol) in DMF (10 mL) at 0° C., NaH (0.25 g, 6.37 mmol) was added and stirred at 0° C. for 30 min. To this mixture, 4-bromo-3-methoxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine (1.3 g, 4.24 mmol) was added and stirred the mixture at room temperature for 6 h.
  • Step-8 To a solution of 4-bromo-3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (0.7 g, 1.64 mmol) in DMF (20 mL), tributyl(vinyl)tin (1.3 g, 4.10 mmol) was added and degassed with nitrogen gas for 5 min. To this mixture, Pd(PPh 3 ) 4 (0.2 g, 0.16 mmol) was added and degassed again with nitrogen gas for 5 min. The mixture was stirred at 90° C. for 16 h.
  • Step-9 A solution of 3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-vinyl-6,7-dihydro-5H-cyclopenta[c]pyridine (0.55 g, 1.48 mmol) in THF (3 mL) and water (3 mL) was cooled to 0° C., Osmium tetroxide (0.41 g, 1.62 mmol) was added and stirred at 0° C. for 15 min. To this mixture, NaIO 4 (1.1 g, 5.18 mmol) was added and stirred the mixture at room temperature for 16 h.
  • Step-10 A solution of 3-methoxy-1-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbaldehyde (90 mg, 0.241 mmol), (S)-piperidine-2-carboxylic acid (37 mg, 0.289 mmol), sodium cyanoborohydride (44 mg, 0.71 mmol) and acetic acid (2 drops) in DMF (5 mL) was stirred at 80° C. for 6 h. After completion, the reaction mixture was poured on ice cold water (10 mL) and extracted with 10% MeOH in DCM (2 ⁇ 30 mL).
  • Step-1 A solution of 5-methoxy-7-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-2,3-dihydro-1H-indene-4-carbaldehyde (150 mg, 0.403 mmol), (S)-morpholine-3-carboxylic acid (158 mg, 1.209 mmol), in DMF (3 mL) and MeOH (3 mL), AcOH (2 drops) was added and stirred for 2 h at room temperature. To this mixture, sodium cyanoborohydride (74 mg, 1.20 mmol) was added and continued stirring for 16 h.
  • PD-L1 Enzyme Assay Homogenous Time-Resolved Fluorescence (HTRF) Binding Assay
  • Table 5 shows the biological activity of compounds of the present invention in PD1/PD-L1 inhibition assay.
  • Compounds having IC50 ⁇ 100 nM are designated as “A”; 100-500 nM are designated as “B”; and >500 nM are designated as “C” respectively.
  • the above-mentioned compounds have potential to be developed as drugs to alleviate the PD1/PD-L1 activity and thus treating cancer, and other diseases or conditions associated with activation of PD1/PD-L1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US16/980,284 2018-03-13 2019-03-13 Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation Active US11529341B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN201841009252 2018-03-13
IN201841009252 2018-03-13
PCT/IN2019/050203 WO2019175897A1 (en) 2018-03-13 2019-03-13 Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation

Publications (2)

Publication Number Publication Date
US20210015810A1 US20210015810A1 (en) 2021-01-21
US11529341B2 true US11529341B2 (en) 2022-12-20

Family

ID=65991865

Family Applications (1)

Application Number Title Priority Date Filing Date
US16/980,284 Active US11529341B2 (en) 2018-03-13 2019-03-13 Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation

Country Status (13)

Country Link
US (1) US11529341B2 (ja)
EP (1) EP3765453A1 (ja)
JP (1) JP7279063B6 (ja)
KR (1) KR20200131845A (ja)
CN (1) CN112105610B (ja)
AU (1) AU2019234185B2 (ja)
BR (1) BR112020018610A2 (ja)
CA (1) CA3093527A1 (ja)
IL (1) IL277183B2 (ja)
MX (1) MX2020009517A (ja)
SG (1) SG11202008950PA (ja)
WO (1) WO2019175897A1 (ja)
ZA (1) ZA202005666B (ja)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12357639B2 (en) 2017-09-22 2025-07-15 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3029256A1 (en) 2016-06-27 2018-01-04 Chemocentryx, Inc. Immunomodulator compounds
WO2018200571A1 (en) 2017-04-25 2018-11-01 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1h-indene analogs and methods using same
JP7185681B2 (ja) 2017-07-28 2022-12-07 ケモセントリックス，インコーポレイティド 免疫調節化合物
CA3071951A1 (en) 2017-08-08 2019-02-14 Chemocentryx, Inc. Macrocyclic immunomodulators
HUE061607T2 (hu) 2017-10-18 2023-07-28 Jubilant Epipad LLC Imidazopiridin vegyületek mint PAD inhibitorok
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
RS65576B1 (sr) 2017-11-24 2024-06-28 Jubilant Episcribe Llc Heterociklična jedinjenja kao inhibitori prmt5
PL3752501T3 (pl) 2018-02-13 2023-08-21 Gilead Sciences, Inc. Inhibitory pd-1/pd-l1
MA51232A (fr) 2018-02-22 2020-10-07 Chemocentryx Inc Indane-amines utiles en tant qu'antagonistes de pd-l1
CN112105610B (zh) 2018-03-13 2024-01-26 朱比连特普罗德尔有限责任公司 作为pd1/pd-l1相互作用/活化的抑制剂的双环化合物
CA3093851A1 (en) 2018-03-29 2019-10-03 Arbutus Biopharma Corporation Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same
TWI712412B (zh) 2018-04-19 2020-12-11 美商基利科學股份有限公司 Pd‐1/pd‐l1抑制劑
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN112955435B (zh) 2018-10-24 2024-09-06 吉利德科学公司 Pd-1/pd-l1抑制剂
WO2020156323A1 (en) 2019-01-31 2020-08-06 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods thereof
WO2020232256A1 (en) 2019-05-15 2020-11-19 Chemocentryx, Inc. Triaryl compounds for treatment of pd-l1 diseases
KR20220024701A (ko) 2019-06-20 2022-03-03 케모센트릭스, 인크. Pd-l1 질환의 치료를 위한 화합물
WO2021007386A1 (en) 2019-07-10 2021-01-14 Chemocentryx, Inc. Indanes as pd-l1 inhibitors
AU2020368393A1 (en) 2019-10-16 2022-04-21 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
PH12022550877A1 (en) 2019-10-16 2023-03-27 Chemocentryx Inc Heteroaryl-biphenyl amines for the treatment of pd-l1 diseases
CN113045523B (zh) * 2019-12-27 2022-09-23 上海泓博智源医药股份有限公司 一种咪唑啉吡啶化合物中间体的制备方法
CN111320606B (zh) * 2020-04-10 2021-07-27 安徽实特医药科技有限公司 苯联吡唑并环类衍生物及其在抗肿瘤药物中的应用
AU2021358123A1 (en) 2020-10-05 2023-06-08 Enliven Inc. 5- and 6-azaindole compounds for inhibition of bcr-abl tyrosine kinases
CA3216045A1 (en) * 2021-04-22 2022-10-27 Naveen SADHU Compounds as pd1/pd-l1 inhibitors and methods thereof
US12018015B2 (en) * 2021-06-18 2024-06-25 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1

Citations (279)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1961595A1 (de) 1968-12-10 1970-06-25 Prodotti Anitibiotici S P A Sp Pyridincarbonylderivate des 7-[Omega(N-Alkylamino)-hydroxyalkyl]-theophyllins und Verfahren zu deren Herstellung
FR2102082A2 (ja) 1970-08-06 1972-04-07 Prodotti Antibiotici Spa
US3970753A (en) 1973-06-12 1976-07-20 Smith Kline & French Laboratories Limited Imidazo[1,2-a]pyridines
US3985881A (en) 1973-12-10 1976-10-12 Merck Patent Gesellschaft Mit Beschrankter Haftung 1(3,4,5-Trimethoxybenzamido methyl) tetrahydro isoquinoline derivatives and a process for their production
DE2832677A1 (de) 1978-07-26 1980-02-07 Bayer Ag Hydroxypropyl-imidazole, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
US4246274A (en) 1978-05-10 1981-01-20 Bayer Aktiengesellschaft Antimycotic hydroxypropyl-imidazoles
US4315855A (en) 1970-10-15 1982-02-16 Basf Aktiengesellschaft Monoazo disperse dyes containing a nitrophenyl group and a homophthalimide group
EP0090269A1 (de) 1982-03-23 1983-10-05 Hoechst Aktiengesellschaft 3-Azolyl-1,2-diaryl-1-halogen-1-propene, ihre Herstellung, ihre Verwendung als Pflanzenschutzmittel und diese Verbindungen enthaltende Präparate
WO1986005519A1 (en) 1985-03-15 1986-09-25 James Summerton Polynucleotide assay reagent and method
EP0218118A1 (de) 1985-09-23 1987-04-15 Hoechst Aktiengesellschaft Arylmethylazole und deren Salze, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung
JPS62187452A (ja) 1986-02-12 1987-08-15 Dainippon Pharmaceut Co Ltd 環状アミン誘導体
EP0239391A2 (en) 1986-03-26 1987-09-30 Kumiai Chemical Industry Co., Ltd. 1,2,6-triphenyl-4(1H)-pyridinone and pyridinethione derivatives, production and uses thereof
US4703056A (en) 1983-01-21 1987-10-27 Alkaloida Vegyeszeti Gyar New alkyl diamine derivatives
EP0259793A1 (de) 1986-09-12 1988-03-16 Dr. Karl Thomae GmbH Neue Naphthylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
EP0301751A1 (en) 1987-07-31 1989-02-01 Takeda Chemical Industries, Ltd. Pyridinium derivatives, their production and use
EP0370852A1 (fr) 1988-11-08 1990-05-30 Synthelabo Dérivés de phényloxypropanolamines, leur préparation et leur application en thérapeutique
DE3901723A1 (de) 1989-01-21 1990-07-26 Bayer Ag Azolyl-derivate
JPH02215809A (ja) 1989-02-17 1990-08-28 Showa Denko Kk オレフィン重合用触媒成分の製造方法及びオレフィンの重合方法
WO1991006537A2 (en) 1989-10-27 1991-05-16 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole- alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase
US5047411A (en) 1988-08-25 1991-09-10 Fujisawa Pharmaceutical Co., Ltd. Benzazole compounds and pharmaceutical composition comprising the same
EP0471236A1 (en) 1990-07-30 1992-02-19 Takeda Chemical Industries, Ltd. Imidazopyridine derivatives and their use
US5179125A (en) 1987-12-03 1993-01-12 Dainippon Pharmaceutical Co., Ltd. N-substituted mercaptopropanamide derivatives
WO1993001157A1 (en) 1991-07-03 1993-01-21 Shionogi & Co., Ltd. Phospholipase a2 inhibitor
EP0533056A2 (de) 1991-09-14 1993-03-24 Hoechst Aktiengesellschaft Substituierte Aminopropane, Verfahren zu ihrer Herstellung und ihre Verwendung als Antimykutiku
EP0535924A1 (en) 1991-09-30 1993-04-07 Merck Frosst Canada Inc. (Bicyclic-azaarylmethoxy)indoles as inhibitors of leukotriene biosynthesis
US5210266A (en) 1987-12-03 1993-05-11 Dainippon Pharmaceutical Co., Ltd. N-substituted mercaptopropanamide derivatives
WO1993012094A1 (de) 1991-12-10 1993-06-24 Hoechst Schering Agrevo Gmbh Pyrimidinyl- oder triazinyl-oxy-(oder -thio)-aldehydderivate, und verwendung als herbizide oder pflanzenwachstumsregulatoren
US5229516A (en) 1989-10-27 1993-07-20 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
WO1993020099A2 (en) 1992-03-27 1993-10-14 Ferring B.V. Cck and/or gastrin receptor ligands
US5273980A (en) 1991-09-30 1993-12-28 Merck Frosst Canada Inc. Bicyclic-azaarylmethoxy) indoles as inhibitors of leukotriene biosynthesis
DE4227522A1 (de) 1992-08-20 1994-02-24 Bayer Ag Lichtpolarisierende Folien und neue dichroitische Farbstoffe hierfür
JPH06184076A (ja) 1992-12-16 1994-07-05 Sankyo Co Ltd 新規ｎ，ｎ’−ジベンゾイルヒドラジン誘導体及び殺虫組成物
US5330989A (en) 1991-10-24 1994-07-19 American Home Products Corporation Heterocycles substituted with biphenyl-3-cyclobutene-1,2-dione derivatives
WO1994022834A1 (en) 1993-03-29 1994-10-13 Zeneca Limited Heterocyclic derivatives as platelet aggregation inhibitors
WO1994022829A2 (en) 1993-04-05 1994-10-13 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
WO1994027971A1 (en) 1993-05-27 1994-12-08 Smithkline Beecham Laboratoires Pharmaceutiques Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines
FR2706895A1 (en) 1993-06-22 1994-12-30 Synthelabo Tetrahydroisoquinoline derivatives, their preparation and their application in therapeutics
WO1995009843A1 (en) 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
WO1995011226A1 (en) 1993-10-20 1995-04-27 Ishihara Sangyo Kaisha Ltd. Substituted benzene derivatives, processes for their production and biocidal composition for control of harmful organisms containing them
US5420289A (en) 1989-10-27 1995-05-30 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
EP0666250A1 (fr) 1994-02-03 1995-08-09 Synthelabo Dérivés de N-(3-aminopropyl)-N-phényl-5,6,7,8-tétrahydronaphtalène-2-carboxamideayant des propriétés neuroprotectrices et anti-ischémiques, leur préparation et leur application en thérapeutique
WO1995021164A1 (en) 1994-02-02 1995-08-10 Eli Lilly And Company Intermediate and process for making
WO1995021832A1 (en) 1994-02-14 1995-08-17 Xenova Limited Pharmaceutical piperazine compounds
JPH07304770A (ja) 1994-05-11 1995-11-21 Kanebo Ltd 新規ベンゾアゼピノン誘導体
WO1996010012A1 (en) 1994-09-29 1996-04-04 The Du Pont Merck Pharmaceutical Company Novel prostaglandin synthase inhibitors
WO1996016040A1 (en) 1994-11-23 1996-05-30 Neurogen Corporation Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands
US5541033A (en) 1995-02-01 1996-07-30 Ocg Microelectronic Materials, Inc. Selected o-quinonediazide sulfonic acid esters of phenolic compounds and their use in radiation-sensitive compositions
US5554621A (en) 1995-06-07 1996-09-10 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: nitrogen heterocyclic derivatives
WO1997009066A1 (fr) 1995-09-08 1997-03-13 Kanebo, Ltd. INHIBITEUR DE SOLUBILISATION DE LIGAND Fas
EP0764640A1 (en) 1995-09-21 1997-03-26 Eli Lilly And Company Selective beta3 adrenergic agonists
WO1997024119A1 (en) 1995-12-29 1997-07-10 Smithkline Beecham Corporation Vitronectin receptor antagonists
WO1997040051A1 (en) 1996-04-24 1997-10-30 Takeda Chemical Industries, Ltd. Fused imidazopyridine derivatives as antihyperlipidemic agents
EP0819977A1 (en) 1996-07-17 1998-01-21 Fuji Photo Film Co., Ltd. Oxonol compound, silver halide photographic material and process for the synthesis of oxonol compound
WO1998017648A1 (en) 1996-10-18 1998-04-30 Xenova Limited Anthranilic acid derivatives as multi drug resistance modulators
WO1998024766A1 (en) 1996-12-06 1998-06-11 Pfizer Inc. 6-phenylpyridyl-2-amine derivatives useful as nos inhibitors
WO1998034609A1 (en) 1997-02-10 1998-08-13 Icn Hungary R.T. Cardioprotective products
WO1998036749A1 (en) 1997-02-21 1998-08-27 Bristol-Myers Squibb Company Tetralone derivatives as antiarrhythmic agents
WO1998038156A1 (en) 1997-02-27 1998-09-03 Takeda Chemical Industries, Ltd. Amine compounds, their production and use as amyloid-beta production inhibitors
DE19717371A1 (de) 1997-04-24 1998-10-29 Basf Ag Propargyl-terminierte, nematische oder cholesterische Polymere
WO1999006387A2 (en) 1997-07-31 1999-02-11 F. Hoffmann-La Roche Ag O-substituted hydroxycumaranone derivatives as antitumor and antimetastatic agents
JPH11119379A (ja) 1997-10-08 1999-04-30 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料および画像形成方法
WO1999032447A2 (en) 1997-12-11 1999-07-01 American Home Products Corporation 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
DE19834751A1 (de) 1998-08-01 2000-02-03 Boehringer Ingelheim Pharma Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2000007978A1 (en) 1998-07-31 2000-02-17 Akzo Nobel N.V. Aminomethylcarboxylic acid derivatives
WO2000023420A1 (fr) 1998-10-20 2000-04-27 Takeda Chemical Industries, Ltd. Derives d'amine aromatique, procede de preparation de ces derives et agents les contenant
WO2000026203A1 (en) 1998-10-30 2000-05-11 Pharmacia & Upjohn S.P.A. 2-ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents
WO2001032178A1 (en) * 1999-10-29 2001-05-10 Novo Nordisk A/S Use of 3,4-substituted piperidines
JP2001233712A (ja) 1999-12-14 2001-08-28 Nippon Kayaku Co Ltd 害虫防除剤
WO2001070731A1 (en) 2000-03-23 2001-09-27 Novartis Ag Decahydro-isoquinolines
WO2001077075A2 (en) 2000-04-06 2001-10-18 Inotek Corporation Inhibitors of inflammation and reperfusion injury
WO2001087293A1 (fr) 2000-05-19 2001-11-22 Takeda Chemical Industries, Ltd. Inhibiteurs de la ?-secretase
WO2002002520A2 (en) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Compounds to treat alzheimer's disease
WO2002002518A2 (en) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Compounds to treat alzheimer's disease
WO2002034716A2 (en) 2000-10-11 2002-05-02 Merck & Co., Inc. Pyrrolidine modulators of ccr5 chemokine receptor activity
US20020094989A1 (en) 2000-10-11 2002-07-18 Hale Jeffrey J. Pyrrolidine modulators of CCR5 chemokine receptor activity
WO2002066478A1 (en) 2001-02-20 2002-08-29 Astrazeneca Ab Antagonists of gonadotropin releasing hormone
WO2002070510A2 (de) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Aminodicarbonsäurederivate mit pharmazeutischen eigenschaften
EP1245565A1 (fr) 2001-03-19 2002-10-02 Les Laboratoires Servier Dérivés d'indénoindolones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2002076964A1 (fr) 2001-03-28 2002-10-03 Sanofi-Synthelabo Derives de n-(arylsulfonyl)beta-aminoacides comportant un groupe aminomethyle substitue, leur procede de preparation et les compositions pharmaceutiques en contenant
WO2002076979A1 (en) 2001-03-27 2002-10-03 Actelion Pharmaceuticals Ltd 1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists
WO2002083673A1 (en) 2001-04-10 2002-10-24 Ortho-Mcneil Pharmaceutical, Inc. 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1 receptor mediated disorders
WO2002088089A1 (fr) 2001-04-19 2002-11-07 Banyu Pharmaceutical Co., Ltd. Derives de spiropiperidine, antagonistes du recepteur de nociceptine les contenant en tant qu'ingredient actif et compositions medicinales
WO2002098869A2 (en) 2001-06-05 2002-12-12 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-disubstituted benzo-fused cycloalkyl urea compounds
WO2002100813A2 (en) 2001-06-07 2002-12-19 Eli Lilly And Company Modulators of peroxisome proliferator activated receptors
US20030018025A1 (en) 1995-06-07 2003-01-23 Neurogen Corporation, Corporation Of The State Of Delaware Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives: new classes of dopamine receptor subtype specific ligands
WO2003035076A1 (en) 2001-10-26 2003-05-01 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dihydroxypyrimidine carboxamide inhibitors of hiv integrase
WO2003037887A1 (en) 2001-11-01 2003-05-08 Astrazeneca Ab Therapeutic isoquinoline compounds
WO2003044016A1 (en) 2001-11-20 2003-05-30 Eli Lilly And Company 3-SUBSTITUTED OXINDOLE β3 AGONISTS
WO2003044017A1 (en) 2001-11-20 2003-05-30 Eli Lilly And Company Beta 3 adrenergic agonists
WO2003066613A1 (en) 2002-02-07 2003-08-14 Novartis Ag N-phenyl-2-pyrimidine-amine derivatives
WO2003084916A2 (en) 2002-04-05 2003-10-16 Warner-Lambert Company Llc Compounds that modulate ppar activity and methods for their preparation
WO2004011430A1 (ja) 2002-07-25 2004-02-05 Yamanouchi Pharmaceutical Co., Ltd. ナトリウムチャネル阻害剤
EP1388342A1 (en) 2002-08-07 2004-02-11 Aventis Pharma Deutschland GmbH Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals
WO2004022558A2 (en) 2002-09-09 2004-03-18 Janssen Pharmaceutica, N.V. Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1 receptor mediated disorders
WO2004035579A1 (ja) 2002-10-15 2004-04-29 Takeda Pharmaceutical Company Limited イミダゾピリジン誘導体、その製造法および用途
WO2004048363A1 (ja) 2002-11-22 2004-06-10 Takeda Pharmaceutical Company Limited イミダゾール誘導体、その製造法および用途
WO2004052846A1 (en) 2002-12-06 2004-06-24 Bayer Healthcare Ag Tetrahydro-naphthalene derivatives
WO2004058679A2 (en) 2002-12-20 2004-07-15 Migenix Corp. Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto
US20040158067A1 (en) * 2002-11-08 2004-08-12 Neurogen Corporation 3-substituted-6-aryl pyridines
WO2004078731A1 (fr) 2003-03-06 2004-09-16 'chemical Diversity Research Institute', Ltd. Acides quinoline-carboxyliques et leurs derives et bibliotheque focalisee
US20040229160A1 (en) 2003-03-11 2004-11-18 Arch Specialty Chemicals, Inc. Novel photosensitive resin compositions
JP2005060247A (ja) 2003-08-12 2005-03-10 Takeda Chem Ind Ltd イソキノリノン誘導体、その製造法および用途
US6887868B2 (en) 2001-09-21 2005-05-03 Pharmacia & Upjohn Company Therapeutic 5-HT ligand compounds
US20050096336A1 (en) * 2003-11-05 2005-05-05 Jean Ackermann Benzannelated derivatives, their manufacture and use as pharmaceutical agents
WO2005058823A1 (ja) 2003-12-17 2005-06-30 Takeda Pharmaceutical Company Limited ウレア誘導体、その製造法及び用途
US20050159334A1 (en) 2004-01-16 2005-07-21 Gluck Oscar S. Method for treating rheumatoid arthritis by inhibiting peptidylarginine deiminase
WO2005092899A1 (en) 2004-03-26 2005-10-06 Methylgene Inc. Inhibitors of histone deacetylase
US20050228014A1 (en) 2004-04-07 2005-10-13 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
WO2005105805A1 (fr) 2004-04-29 2005-11-10 'chemical Diversity Research Institute', Ltd. Carbamoylase-heterocycles anneles, bibliotheque focalisee, compositions pharmaceutiques et procedes de fabrication correspondants
WO2005123703A2 (en) 2004-06-17 2005-12-29 Addex Pharmaceuticals Sa Alkynyl derivatives as modulators of metabotropic glutamate receptors
WO2006048330A1 (en) 2004-11-08 2006-05-11 Evotec Ag 11βετα-hsd1 inhibitors
WO2006062224A1 (ja) 2004-12-07 2006-06-15 Takeda Pharmaceutical Company Limited カルボキサミド誘導体
WO2006069125A1 (en) 2004-12-22 2006-06-29 Theravance, Inc. Indazole-carboxamide compounds
WO2006102588A1 (en) 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006105971A1 (de) 2005-04-08 2006-10-12 Grünenthal GmbH Substituierte 5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyridin-2-ylamin-verbindungen und deren verwendung zur herstellung von arzneimitteln
WO2006125119A1 (en) 2005-05-17 2006-11-23 Sarcode Corporation Compositions and methods for treatment of eye disorders
US20060270686A1 (en) 2003-08-29 2006-11-30 Martha Kelly Anti-cancer agents and uses thereof
WO2006126939A1 (en) 2005-05-23 2006-11-30 Astrazeneca Ab Novel 8-sulfonylamino-3 aminosubstituted chroman or tetrahydronaphtalene derivatives modulating the 5ht6 receptor
WO2006130707A2 (en) 2005-06-02 2006-12-07 Jenrin Discovery Mao-b inhibitors useful for treating obesity
WO2006133104A2 (en) 2005-06-07 2006-12-14 Theravance, Inc. Benzoimidazolone-carboxamide compounds as 5-ht4 receptor agonists
WO2007073503A2 (en) 2005-12-21 2007-06-28 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity and use thereof
WO2007087548A2 (en) 2006-01-25 2007-08-02 Smithkline Beecham Corporation Chemical compounds
US20070191371A1 (en) 2006-02-14 2007-08-16 Kalypsys, Inc. Heterocyclic modulators of ppar
US20070219218A1 (en) 2004-07-16 2007-09-20 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2007106469A2 (en) 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
WO2007105989A2 (en) 2006-03-14 2007-09-20 Ivashchenko, Andrey Alexandrovich 1-oxo-3-(1h-indole)-3-il-1,2,3,4-tetrahydroisoxynolines, methods for the production thereof, combinatoric library and focused library
WO2007133108A1 (fr) 2006-05-12 2007-11-22 Chemdiv, Ink. Composition pharmaceutique, procédé de fabrication et d'application
WO2008000408A1 (en) 2006-06-28 2008-01-03 Sanofi-Aventis Cxcr2 antagonists
WO2008008059A1 (en) 2006-07-12 2008-01-17 Locus Pharmaceuticals, Inc. Anti-cancer agents ans uses thereof
WO2008022945A1 (de) 2006-08-19 2008-02-28 Boehringer Ingelheim International Gmbh Arylsulfonamide mit analgetischer wirkung
WO2008051757A1 (en) 2006-10-20 2008-05-02 Irm Llc Compositions and methods for modulating c-kit and pdgfr receptors
WO2008064320A2 (en) 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity
WO2008065500A2 (en) 2006-11-30 2008-06-05 Pfizer Products Inc. Heteroaryl amides as type i glycine transport inhibitors
WO2008066789A2 (en) 2006-11-27 2008-06-05 H. Lundbeck A/S Heteroaryl amide derivatives
WO2008079988A2 (en) 2006-12-22 2008-07-03 Novartis Ag Quinazolines for pdk1 inhibition
WO2008104077A1 (en) 2007-02-28 2008-09-04 Methylgene Inc. Small molecule inhibitors of protein arginine methyltransferases (prmts)
WO2008112715A2 (en) 2007-03-12 2008-09-18 Vm Discovery Inc. Novel agents of calcium ion channel modulators
WO2008121687A2 (en) 2007-03-28 2008-10-09 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
WO2008123582A1 (ja) 2007-04-04 2008-10-16 Kowa Company, Ltd. テトラヒドロイソキノリン化合物
WO2008135526A1 (en) 2007-05-02 2008-11-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides as factor xa inhibitors
US20080280891A1 (en) 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
JP2008280344A (ja) 2007-04-12 2008-11-20 Sumitomo Chemical Co Ltd ヒドラジド化合物及びそれを含有する有害節足動物防除剤
WO2008156142A1 (ja) 2007-06-20 2008-12-24 Mitsubishi Tanabe Pharma Corporation 新規なマロン酸スルホンアミド誘導体およびその医薬用途
WO2009010925A2 (en) 2007-07-17 2009-01-22 Alla Chem, Llc Annelated azaheterocyclic amides containing a pyrimidine fragment and method for the production and use thereof
WO2009023179A2 (en) 2007-08-10 2009-02-19 Genelabs Technologies, Inc. Nitrogen containing bicyclic chemical entities for treating viral infections
US20090069373A1 (en) 2007-02-28 2009-03-12 Wyeth Quinoline Acids
WO2009038842A2 (en) 2007-06-15 2009-03-26 Mission Pharmacal Co. Methods and compositions to inhibit edema factor and adenylyl cyclase
WO2009048152A2 (en) 2007-10-11 2009-04-16 Sumitomo Chemical Company, Limited Unsaturated imine compound and use thereof for pest control
WO2009054914A1 (en) 2007-10-19 2009-04-30 Sarcode Corporation Compositions and methods for treatment of diabetic retinopathy
WO2009080351A1 (en) 2007-12-21 2009-07-02 Santhera Pharmaceuticals (Schweiz) Ag Compounds with anti-emetic effect
WO2009104819A1 (en) 2008-02-22 2009-08-27 Otsuka Pharmaceutical Co., Ltd. Benzodiazepine compound and pharmaceutical composition
JP2009209090A (ja) 2008-03-04 2009-09-17 Mitsui Chemicals Inc 殺虫剤及び該殺虫剤に含まれる化合物、並びに該化合物の使用方法
WO2009112651A1 (fr) 2008-01-02 2009-09-17 Sanofi-Aventis Dérivés d'mtoazo[1,2-a]pyridine-2-carboxamides, leur préparation et leur application en thérapeutique
US20090264433A1 (en) 2008-04-21 2009-10-22 Institute For Oneworld Health Compounds, Compositions and Methods Comprising Triazine Derivatives
RU2371444C1 (ru) 2008-01-24 2009-10-27 Андрей Александрович Иващенко ФУРО- И ТИЕНО[2,3-b]-ХИНОЛИН-2-КАРБОКСАМИДЫ, СПОСОБ ПОЛУЧЕНИЯ И ПРОТИВОТУБЕРКУЛЕЗНАЯ АКТИВНОСТЬ
WO2009137309A2 (en) 2008-05-01 2009-11-12 Travel Tech Systems, Llc Process and system to determine commercial airline arrivals
WO2009140101A2 (en) 2008-05-12 2009-11-19 Boehringer Ingelheim International Gmbh Imidazopyridine compounds useful as mmp-13 inhibitors
JP2009274984A (ja) 2008-05-14 2009-11-26 Sumitomo Chemical Co Ltd 化合物、光学フィルムおよび光学フィルムの製造方法
WO2009153313A1 (en) 2008-06-20 2009-12-23 Novartis Ag 2 -arylaminoquinazolines for treating proliferative diseases
WO2010048207A2 (en) 2008-10-21 2010-04-29 Metabolex, Inc. Aryl gpr120 receptor agonists and uses thereof
EP2194035A2 (de) 2008-12-06 2010-06-09 Saltigo GmbH Hydroxytetralone
WO2010075973A1 (de) 2008-12-17 2010-07-08 Grünenthal GmbH Substituierte 4-(1,2,3,4-tetrahydroisochinolin-2-yl)-4-oxo-buttersäureamide als kcnq2/3 modulatoren
WO2010077680A2 (en) 2008-12-08 2010-07-08 Vm Discovery Inc. Compositions of protein receptor tyrosine kinase inhibitors
WO2010091409A1 (en) 2009-02-09 2010-08-12 Glaxosmithkline Llc Certain nitrogen containing bicyclic chemical entities for treating viral infections
WO2010098495A1 (en) 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Imidazolylpyrazine derivatives
CN101838264A (zh) 2009-03-16 2010-09-22 住友化学株式会社 化合物、光学膜和光学膜的制造方法
US20100249127A1 (en) 2009-03-31 2010-09-30 Arqule, Inc. Substituted indolo-pyridinone compounds
WO2010151799A2 (en) 2009-06-26 2010-12-29 University Of Massachusetts Compounds for modulating rna binding proteins and uses therefor
WO2011023989A1 (en) 2009-08-24 2011-03-03 Sterix Limited Aromatase inhibitor
JP2011063589A (ja) 2009-08-21 2011-03-31 Otsuka Pharmaceut Co Ltd 医薬組成物
WO2011086178A1 (en) 2010-01-15 2011-07-21 Hybrigenics Sa Amidoacridine derivatives useful as selective inhibitors of ubiquitin specific protease 7
WO2011100380A1 (en) 2010-02-11 2011-08-18 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
WO2011123751A2 (en) 2010-04-02 2011-10-06 Amgen Inc. Heterocyclic compounds and their uses
JP2011207765A (ja) 2009-03-16 2011-10-20 Sumitomo Chemical Co Ltd 化合物、光学フィルム及び光学フィルムの製造方法
WO2012006202A1 (en) 2010-07-07 2012-01-12 Boehringer Ingelheim International Gmbh Rho kinase inhibitors
WO2012006203A1 (en) 2010-07-07 2012-01-12 Boehringer Ingelheim International Gmbh N-cyclyl-3 - (cyclylcarbonylaminomethyl) benzamide derivatives as rho kinase inhibitors
WO2012022045A1 (en) 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
WO2012022265A1 (en) 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
US8148408B2 (en) 2008-05-09 2012-04-03 Abbott Laboratories Selective substituted pyridine ligands for neuronal nicotinic receptors
WO2012058133A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. Isoindolinone pde10 inhibitors
WO2012087833A1 (en) 2010-12-22 2012-06-28 Abbott Laboratories Hepatitis c inhibitors and uses thereof
WO2013002879A1 (en) 2011-06-29 2013-01-03 President And Fellows Of Harvard College Small molecule cd38 inhibitors and methods of using same
WO2013000994A1 (en) 2011-06-30 2013-01-03 Abbott Gmbh & Co. Kg Novel inhibitor compounds of phosphodiesterase type 10a
WO2013002880A1 (en) 2011-06-29 2013-01-03 The General Hospital Corporation Compositions and methods for enhancing bioenergetic status in female germ cells
WO2013018371A1 (ja) 2011-08-03 2013-02-07 杏林製薬株式会社 ビアリールエステル誘導体、及びそれを含む医薬
WO2013025733A1 (en) 2011-08-15 2013-02-21 Intermune, Inc. Lysophosphatidic acid receptor antagonists
WO2013068470A1 (en) 2011-11-09 2013-05-16 Abbott Gmbh & Co. Kg Inhibitors of phosphodiesterase type 10a
WO2013096055A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096059A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096049A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096060A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096681A1 (en) 2011-12-22 2013-06-27 Gilead Sciences, Inc. Pyrazolo[1,5-a]pyrimidines as antiviral agents
WO2013120464A1 (en) 2012-02-17 2013-08-22 Zentiva, K.S. A process for the preparation of rivaroxaban based on saving of 1,1'-carbonyl diimidazole.
WO2013127729A1 (en) 2012-02-27 2013-09-06 Boehringer Ingelheim International Gmbh 6 - alkynyl pyridines as smac mimetics
WO2013174895A1 (en) 2012-05-24 2013-11-28 Cellzome Limited Heterocyclyl pyrimidine analogues as tyk2 inhibitors
WO2013178810A1 (en) 2012-05-31 2013-12-05 Universite De Strasbourg Ornithine- and lysine-derivatives for the treatment of pain
WO2013192430A2 (en) 2012-06-20 2013-12-27 The Regents Of The University Of California Dynamic biomimetic synzyme catalyst, catalysis, and catalytic systems
WO2014013182A1 (fr) 2012-07-20 2014-01-23 Metabrain Research Derive d'imidazopyridine utiles dans le traitement du diabete
WO2014015905A1 (en) 2012-07-26 2014-01-30 Glaxo Group Limited 2 - (azaindol- 2 -yl) benz imidazoles as pad4 inhibitors
US8642660B2 (en) 2007-12-21 2014-02-04 The University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2014031872A2 (en) 2012-08-23 2014-02-27 The Broad Institute, Inc. Small molecule inhibitors for treating parasitic infections
WO2014031986A1 (en) 2012-08-24 2014-02-27 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
WO2014077321A1 (ja) 2012-11-15 2014-05-22 高砂香料工業株式会社 アルミニウム触媒
WO2014100764A2 (en) 2012-12-21 2014-06-26 Epizyme, Inc. Methods of inhibiting prmt5
WO2014100719A2 (en) 2012-12-21 2014-06-26 Epizyme, Inc. Prmt5 inhibitors and uses thereof
WO2014152018A1 (en) 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
WO2015011397A1 (fr) 2013-07-23 2015-01-29 Les Laboratoires Servier Nouveaux dérivés d'indolizine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2015031295A1 (en) 2013-08-27 2015-03-05 Bristol-Myers Squibb Company Ido inhibitors
WO2015034820A1 (en) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015086527A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused tricyclic imidazole derivatives as modulators of tnf activity
WO2015086512A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of tnf activity
US9067898B1 (en) 2014-03-07 2015-06-30 Janssen Pharmaceutica Nv Isothiazole derivatives as GPR120 agonists for the treatment of type II diabetes
WO2015108038A1 (ja) 2014-01-17 2015-07-23 第一三共株式会社 エチレングリコール化合物
WO2015140051A1 (en) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Heteroaryl sik inhibitors
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
WO2016008433A1 (en) 2014-07-17 2016-01-21 Sunshine Lake Pharma Co., Ltd. Substituted urea derivatives and pharmaceutical uses thereof
WO2016031815A1 (ja) 2014-08-26 2016-03-03 武田薬品工業株式会社 複素環化合物
WO2016034675A1 (en) 2014-09-03 2016-03-10 Ctxt Pty Ltd Tetrahydroisoquinoline derived prmt5-inhibitors
WO2016036636A1 (en) 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
CN105461693A (zh) 2014-09-26 2016-04-06 广东东阳光药业有限公司 Crth2拮抗剂化合物及其用途
WO2016051306A2 (en) 2014-10-03 2016-04-07 Maheshwari Divya Novel anthranilic acid derivatives
WO2016102727A1 (es) 2014-12-22 2016-06-30 Consejo Superior De Investigaciones Científicas (Csic) Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos
US20160229816A1 (en) * 2013-07-17 2016-08-11 Otsuka Pharmaceutical Co., Ltd. Cyanotriazole compounds
WO2016185279A1 (en) 2015-05-21 2016-11-24 Glaxosmithkline Intellectual Property Development Limited Benzoimidazole derivatives as pad4 inhibitors
EP3112362A1 (en) 2014-02-27 2017-01-04 ONO Pharmaceutical Co., Ltd. Compound exhibiting selective ep2 agonist activity
WO2017024180A1 (en) 2015-08-06 2017-02-09 Amgen Inc. Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2017025510A1 (en) 2015-08-12 2017-02-16 Syngenta Participations Ag Microbiocidal heterobicyclic derivatives
WO2017042182A1 (en) 2015-09-08 2017-03-16 F. Hoffmann-La Roche Ag Tricyclic pi3k inhibitor compounds and methods of use
US20170105971A1 (en) 2015-07-03 2017-04-20 Anca CATRINA Methods and compounds for the treatment of bone loss and/or pain
WO2017068412A1 (en) 2015-10-21 2017-04-27 Otsuka Pharmaceutical Co., Ltd. Benzolactam compounds as protein kinase inhibitors
WO2017106634A1 (en) 2015-12-17 2017-06-22 Incyte Corporation N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators
US20170174672A1 (en) 2015-12-22 2017-06-22 AbbVie Deutschland GmbH & Co. KG Fused (hetero)cyclic compounds as s1p modulators
WO2017118762A1 (en) 2016-01-08 2017-07-13 Rijksuniversiteit Groningen Inhibitors of the pd-1/pd-l1 protein/protein interaction
US9732066B2 (en) 2011-08-18 2017-08-15 Nippon Shiny Aku Co., Ltd. Heterocyclic derivative and pharmaceutical drug
CN107056630A (zh) 2017-01-23 2017-08-18 合肥工业大学 一种茚满类衍生物及其合成方法和在医药上的用途
WO2017147102A1 (en) 2016-02-23 2017-08-31 Padlock Therapeutics, Inc. Heteroaryl inhibitors of pad4
CN107163044A (zh) 2017-06-19 2017-09-15 广东药科大学 一类具有蛋白酶修饰活性的萘乙二酮化合物及其衍生物
WO2017216281A1 (en) 2016-06-16 2017-12-21 Janssen Sciences Ireland Uc Heterocyclic compounds as antibacterials
WO2018002848A1 (en) 2016-06-30 2018-01-04 VIIV Healthcare UK (No.5) Limited Azadecalin derivatives as inhibitors of human immunodeficiency virus replication
WO2018019204A1 (zh) 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物
WO2018026971A1 (en) 2016-08-03 2018-02-08 Arising International, Llc Symmetric or semi-symmetric compounds useful as immunomodulators
WO2018112843A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
WO2018119036A1 (en) 2016-12-21 2018-06-28 Janssen Biotech, Inc. Pyrazole derivatives as malt1 inhibitors
WO2018121610A1 (zh) 2016-12-27 2018-07-05 山东大学 针对Smoothened突变株的刺猬通路抑制剂
CN108358917A (zh) 2018-04-24 2018-08-03 北京市结核病胸部肿瘤研究所 含有碱性稠环片段的咪唑并[1,2-a]吡啶-3-酰胺类化合物及其制备方法
WO2018183411A1 (en) 2017-03-28 2018-10-04 The Regents Of The University Of Michigan Small molecule dcn1 inhibitors and therapeutic methods using the same
WO2018208985A2 (en) 2017-05-10 2018-11-15 Forge Therapeutics, Inc. Antibacterial compounds
WO2018234342A1 (en) 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag ISOINDOLINONE DERIVATIVES AS MODULATORS OF IRAK4
WO2019007696A1 (en) 2017-07-06 2019-01-10 Galapagos Nv NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF FIBROSIS
WO2019058393A1 (en) 2017-09-22 2019-03-28 Jubilant Biosys Limited HETEROCYCLIC COMPOUNDS AS INHIBITORS OF PAD
WO2019079783A1 (en) 2017-10-20 2019-04-25 Vanderbilt University ANTAGONISTS OF THE MUSCARINIC RECEPTOR OF ACETYLCHOLINE M4
WO2019077631A1 (en) 2017-10-18 2019-04-25 Jubilant Biosys Limited IMIDAZO-PYRIDINE COMPOUNDS FOR USE AS PAD INHIBITORS
WO2019087214A1 (en) 2017-11-06 2019-05-09 Jubilant Biosys Limited Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation
WO2019102494A1 (en) 2017-11-24 2019-05-31 Jubilant Biosys Limited Heterocyclic compounds as prmt5 inhibitors
WO2019126081A1 (en) 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Amide substituted indole compounds useful as tlr inhibitors
CN110105299A (zh) 2019-01-23 2019-08-09 中山大学 一种含芳醚取代恶唑烷酮羧酸酯类衍生物及其制备方法和应用
WO2019154047A1 (zh) 2018-02-07 2019-08-15 复旦大学 烷氧基苯并五元(六元)杂环胺类化合物及其药物用途
WO2019160014A1 (ja) 2018-02-14 2019-08-22 富士フイルム株式会社 重合性液晶組成物、光学異方性膜、光学フィルム、偏光板および画像表示装置
JP2019156770A (ja) 2018-03-14 2019-09-19 日本化薬株式会社 ベンゾアゾール化合物、並びにこれを含んだ顔料組成物
WO2019175897A1 (en) 2018-03-13 2019-09-19 Jubilant Biosys Limited Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation
WO2019205147A1 (zh) 2018-04-28 2019-10-31 上海璃道医药科技有限公司 包含苯并含氧脂肪环结构的氨基乙酰胺类化合物及其用途
WO2019213234A1 (en) 2018-05-01 2019-11-07 The Trustees Of Columbia University In The City Of New York Triazolopyrimidines, their preparation and use
WO2020028723A1 (en) 2018-08-01 2020-02-06 The Trustees Of Columbia University In The City Of New York Rbp4 antagonists for treatment and prevention of non-alcoholic fatty liver disease and gout
WO2020029980A1 (en) 2018-08-06 2020-02-13 Moexa Pharmaceuticals Limited Smad3 inhibitors
WO2020045216A1 (ja) 2018-08-28 2020-03-05 富士フイルム株式会社 積層体および画像表示装置
CN110963997A (zh) 2018-09-28 2020-04-07 四川科伦博泰生物医药股份有限公司 杂环酰胺类化合物、包含其的药物组合物及其制备方法和用途
WO2020083971A2 (en) 2018-10-24 2020-04-30 Bayer Animal Health Gmbh New anthelmintic compounds
WO2020092394A1 (en) 2018-10-30 2020-05-07 Gilead Sciences, Inc. Imidazopyridine derivatives as alpha4beta7 integrin inhibitors
CN111606904A (zh) 2020-04-07 2020-09-01 广州医科大学 氮杂吲哚类化合物及其应用
WO2020201773A1 (en) 2019-04-05 2020-10-08 Storm Therapeutics Ltd Mettl3 inhibitory compounds
WO2020246910A1 (ru) 2019-06-03 2020-12-10 Александл Васильевич ИВАЩЕНКО АНЕЛИРОВАННЫЕ 9-ГИДРОКСИ- 1,8 - ДИОКСО- 1, 3,4, 8 -ТЕТРАГИДРО-2Н-ПИРИДО [1,2-α] ПИРАЗИН-7 - КАРБОКСАМИДЫ - ИНГИБИТОРЫ ИНТЕГРАЗЫ ВИЧ
WO2021014949A1 (ja) 2019-07-24 2021-01-28 住友化学株式会社 重合性液晶混合組成物、位相差板、楕円偏光板および有機ｅｌ表示装置
WO2021018858A1 (en) 2019-07-29 2021-02-04 Les Laboratoires Servier 6,7-dihydro-5h-pyrido[2,3-c]pyridazine derivatives and related compounds as bcl-xl protein inhibitors and pro-apoptotic agents for treating cancer
WO2021028810A1 (en) 2019-08-09 2021-02-18 Inorbit Therapeutics Ab Sulfinic acid compounds as free fatty acid receptor agonists
WO2021060432A1 (ja) 2019-09-27 2021-04-01 富士フイルム株式会社 液晶組成物、光学異方性層、光学フィルム、偏光板および画像表示装置
JP2021054909A (ja) 2019-09-27 2021-04-08 富士フイルム株式会社 液晶組成物、光学異方性層、光学フィルム、偏光板および画像表示装置
WO2021096241A1 (en) 2019-11-15 2021-05-20 Yuhan Corporation Novel compounds having inhibitory activity against glucosylceramide synthase or pharmaceutically acceptable salt thereof, processes for preparing the same, and pharmaceutical compositions comprising the same
WO2021096238A1 (en) 2019-11-15 2021-05-20 Yuhan Corporation Novel derivatives having 2,3-dihydro-1h-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
US11230526B1 (en) * 2018-03-06 2022-01-25 Janssen Pharmaceutica Nv Cylcoalkenyl derivatives useful as agonists of the GPR120 and/or GPR40 receptors

Patent Citations (308)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1961595A1 (de) 1968-12-10 1970-06-25 Prodotti Anitibiotici S P A Sp Pyridincarbonylderivate des 7-[Omega(N-Alkylamino)-hydroxyalkyl]-theophyllins und Verfahren zu deren Herstellung
US3565896A (en) 1968-12-10 1971-02-23 Prodotti Antibiotici Spa Pyridinecarbonyl derivatives of 7-(omega-(n-alkyl-n-optionally hydroxyalkyl substituted amino) - hydroxyalkyl)theophylline
GB1230663A (ja) 1968-12-10 1971-05-05
FR2102082A2 (ja) 1970-08-06 1972-04-07 Prodotti Antibiotici Spa
GB1356789A (en) 1970-08-06 1974-06-12 Prodotti Antibiotici Spa Derivatives of theophylline
US4315855A (en) 1970-10-15 1982-02-16 Basf Aktiengesellschaft Monoazo disperse dyes containing a nitrophenyl group and a homophthalimide group
US3970753A (en) 1973-06-12 1976-07-20 Smith Kline & French Laboratories Limited Imidazo[1,2-a]pyridines
US3985881A (en) 1973-12-10 1976-10-12 Merck Patent Gesellschaft Mit Beschrankter Haftung 1(3,4,5-Trimethoxybenzamido methyl) tetrahydro isoquinoline derivatives and a process for their production
US4246274A (en) 1978-05-10 1981-01-20 Bayer Aktiengesellschaft Antimycotic hydroxypropyl-imidazoles
DE2832677A1 (de) 1978-07-26 1980-02-07 Bayer Ag Hydroxypropyl-imidazole, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
EP0090269A1 (de) 1982-03-23 1983-10-05 Hoechst Aktiengesellschaft 3-Azolyl-1,2-diaryl-1-halogen-1-propene, ihre Herstellung, ihre Verwendung als Pflanzenschutzmittel und diese Verbindungen enthaltende Präparate
DE3210570A1 (de) 1982-03-23 1983-10-06 Hoechst Ag 3-azolyl-1,2-diaryl-1-halogen-1-propene, ihre herstellung, ihre verwendung als pflanzenschutzmittel und diese verbindungen enthaltende praeparate
US4495191A (en) 1982-03-23 1985-01-22 Hoechst Aktiengesellschaft Fungicidal 3-1,2,4-triazol-1-yl-1,2-diaryl-1-halogeno-prop-1-ene derivatives, compositions, and method of use
US4703056A (en) 1983-01-21 1987-10-27 Alkaloida Vegyeszeti Gyar New alkyl diamine derivatives
WO1986005519A1 (en) 1985-03-15 1986-09-25 James Summerton Polynucleotide assay reagent and method
EP0218118A1 (de) 1985-09-23 1987-04-15 Hoechst Aktiengesellschaft Arylmethylazole und deren Salze, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und ihre Verwendung
DE3628545A1 (de) 1985-09-23 1987-04-23 Hoechst Ag Arylmethylazole und deren salze, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung
US5100890A (en) 1985-09-23 1992-03-31 Hoechst Aktiengesellschaft Arylmethylazoles and their salts, agents which contain these compounds, and their use
JPS62187452A (ja) 1986-02-12 1987-08-15 Dainippon Pharmaceut Co Ltd 環状アミン誘導体
EP0239391A2 (en) 1986-03-26 1987-09-30 Kumiai Chemical Industry Co., Ltd. 1,2,6-triphenyl-4(1H)-pyridinone and pyridinethione derivatives, production and uses thereof
US4757081A (en) 1986-03-26 1988-07-12 Kumiai Chemical Industry Co., Ltd. 1,2,6-triphenyl-4(1H)-pyridinone derivatives, and uses as fungicidal agents
US4871751A (en) 1986-03-26 1989-10-03 Kumai Chemical Industry Co., Ltd. 1,2,6-Triphenyl-4(1H)-pyridinone derivatives, and their use as fungicides
EP0259793A1 (de) 1986-09-12 1988-03-16 Dr. Karl Thomae GmbH Neue Naphthylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US4871735A (en) 1986-09-12 1989-10-03 Dr. Karl Thomae Gmbh Naphthyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them
EP0301751A1 (en) 1987-07-31 1989-02-01 Takeda Chemical Industries, Ltd. Pyridinium derivatives, their production and use
US4962113A (en) 1987-07-31 1990-10-09 Takeda Chemical Industries, Ltd Pyridinium derivatives, their production and use
US5210266A (en) 1987-12-03 1993-05-11 Dainippon Pharmaceutical Co., Ltd. N-substituted mercaptopropanamide derivatives
US5179125A (en) 1987-12-03 1993-01-12 Dainippon Pharmaceutical Co., Ltd. N-substituted mercaptopropanamide derivatives
US5047411A (en) 1988-08-25 1991-09-10 Fujisawa Pharmaceutical Co., Ltd. Benzazole compounds and pharmaceutical composition comprising the same
US5001132A (en) 1988-11-08 1991-03-19 Synthelabo Phenyloxypropanolamine derivatives and their application in therapeutics
EP0370852A1 (fr) 1988-11-08 1990-05-30 Synthelabo Dérivés de phényloxypropanolamines, leur préparation et leur application en thérapeutique
US5010094A (en) 1989-01-21 1991-04-23 Bayer Aktiengesellschaft Imidazolyl compounds and their use as fungicides
DE3901723A1 (de) 1989-01-21 1990-07-26 Bayer Ag Azolyl-derivate
JPH02215809A (ja) 1989-02-17 1990-08-28 Showa Denko Kk オレフィン重合用触媒成分の製造方法及びオレフィンの重合方法
WO1991006537A2 (en) 1989-10-27 1991-05-16 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole- alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase
US5420289A (en) 1989-10-27 1995-05-30 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
US5229516A (en) 1989-10-27 1993-07-20 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
EP0471236A1 (en) 1990-07-30 1992-02-19 Takeda Chemical Industries, Ltd. Imidazopyridine derivatives and their use
US5244908A (en) 1990-07-30 1993-09-14 Takeda Chemical Industries, Ltd. Imidazopyridine derivatives and their pharmaceutical use
WO1993001157A1 (en) 1991-07-03 1993-01-21 Shionogi & Co., Ltd. Phospholipase a2 inhibitor
EP0533056A2 (de) 1991-09-14 1993-03-24 Hoechst Aktiengesellschaft Substituierte Aminopropane, Verfahren zu ihrer Herstellung und ihre Verwendung als Antimykutiku
EP0535924A1 (en) 1991-09-30 1993-04-07 Merck Frosst Canada Inc. (Bicyclic-azaarylmethoxy)indoles as inhibitors of leukotriene biosynthesis
US5273980A (en) 1991-09-30 1993-12-28 Merck Frosst Canada Inc. Bicyclic-azaarylmethoxy) indoles as inhibitors of leukotriene biosynthesis
US5330989A (en) 1991-10-24 1994-07-19 American Home Products Corporation Heterocycles substituted with biphenyl-3-cyclobutene-1,2-dione derivatives
WO1993012094A1 (de) 1991-12-10 1993-06-24 Hoechst Schering Agrevo Gmbh Pyrimidinyl- oder triazinyl-oxy-(oder -thio)-aldehydderivate, und verwendung als herbizide oder pflanzenwachstumsregulatoren
WO1993020099A2 (en) 1992-03-27 1993-10-14 Ferring B.V. Cck and/or gastrin receptor ligands
WO1994001407A2 (en) 1992-07-10 1994-01-20 American Home Products Corporation Indole and indene derivatives as pla2 and lipoxygenase inhibitors
DE4227522A1 (de) 1992-08-20 1994-02-24 Bayer Ag Lichtpolarisierende Folien und neue dichroitische Farbstoffe hierfür
JPH06184076A (ja) 1992-12-16 1994-07-05 Sankyo Co Ltd 新規ｎ，ｎ’−ジベンゾイルヒドラジン誘導体及び殺虫組成物
WO1994022834A1 (en) 1993-03-29 1994-10-13 Zeneca Limited Heterocyclic derivatives as platelet aggregation inhibitors
WO1994022829A2 (en) 1993-04-05 1994-10-13 Synaptic Pharmaceutical Corporation Dihydropyridines and new uses thereof
WO1994027971A1 (en) 1993-05-27 1994-12-08 Smithkline Beecham Laboratoires Pharmaceutiques Anti-arrhythmic n-substituted 3-benzazepines or isoquinolines
FR2706895A1 (en) 1993-06-22 1994-12-30 Synthelabo Tetrahydroisoquinoline derivatives, their preparation and their application in therapeutics
WO1995009843A1 (en) 1993-10-07 1995-04-13 Agouron Pharmaceuticals, Inc. Hiv protease inhibitors
WO1995011226A1 (en) 1993-10-20 1995-04-27 Ishihara Sangyo Kaisha Ltd. Substituted benzene derivatives, processes for their production and biocidal composition for control of harmful organisms containing them
WO1995021164A1 (en) 1994-02-02 1995-08-10 Eli Lilly And Company Intermediate and process for making
EP0666250A1 (fr) 1994-02-03 1995-08-09 Synthelabo Dérivés de N-(3-aminopropyl)-N-phényl-5,6,7,8-tétrahydronaphtalène-2-carboxamideayant des propriétés neuroprotectrices et anti-ischémiques, leur préparation et leur application en thérapeutique
US5550162A (en) 1994-02-03 1996-08-27 Synthelabo N-(-3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydro-naphthalene-2-carboxamide derivatives, their preparation and their therapeutic use
US5663183A (en) 1994-02-03 1997-09-02 Synthelabo N-(3-Aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide derivatives, their preparation and their therapeutic use
WO1995021832A1 (en) 1994-02-14 1995-08-17 Xenova Limited Pharmaceutical piperazine compounds
JPH07304770A (ja) 1994-05-11 1995-11-21 Kanebo Ltd 新規ベンゾアゼピノン誘導体
WO1996010012A1 (en) 1994-09-29 1996-04-04 The Du Pont Merck Pharmaceutical Company Novel prostaglandin synthase inhibitors
WO1996016040A1 (en) 1994-11-23 1996-05-30 Neurogen Corporation Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands
US5541033A (en) 1995-02-01 1996-07-30 Ocg Microelectronic Materials, Inc. Selected o-quinonediazide sulfonic acid esters of phenolic compounds and their use in radiation-sensitive compositions
US5547814A (en) 1995-02-01 1996-08-20 Ocg Microelectronic Materials, Inc. O-quinonediazide sulfonic acid esters of phenolic compounds and their use in forming positive images
EP0747378A1 (en) 1995-06-07 1996-12-11 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists
US5554621A (en) 1995-06-07 1996-09-10 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: nitrogen heterocyclic derivatives
US20030018025A1 (en) 1995-06-07 2003-01-23 Neurogen Corporation, Corporation Of The State Of Delaware Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives: new classes of dopamine receptor subtype specific ligands
WO1997009066A1 (fr) 1995-09-08 1997-03-13 Kanebo, Ltd. INHIBITEUR DE SOLUBILISATION DE LIGAND Fas
EP0764640A1 (en) 1995-09-21 1997-03-26 Eli Lilly And Company Selective beta3 adrenergic agonists
WO1997024119A1 (en) 1995-12-29 1997-07-10 Smithkline Beecham Corporation Vitronectin receptor antagonists
WO1997040051A1 (en) 1996-04-24 1997-10-30 Takeda Chemical Industries, Ltd. Fused imidazopyridine derivatives as antihyperlipidemic agents
EP0819977A1 (en) 1996-07-17 1998-01-21 Fuji Photo Film Co., Ltd. Oxonol compound, silver halide photographic material and process for the synthesis of oxonol compound
WO1998017648A1 (en) 1996-10-18 1998-04-30 Xenova Limited Anthranilic acid derivatives as multi drug resistance modulators
WO1998024766A1 (en) 1996-12-06 1998-06-11 Pfizer Inc. 6-phenylpyridyl-2-amine derivatives useful as nos inhibitors
WO1998034609A1 (en) 1997-02-10 1998-08-13 Icn Hungary R.T. Cardioprotective products
WO1998036749A1 (en) 1997-02-21 1998-08-27 Bristol-Myers Squibb Company Tetralone derivatives as antiarrhythmic agents
WO1998038156A1 (en) 1997-02-27 1998-09-03 Takeda Chemical Industries, Ltd. Amine compounds, their production and use as amyloid-beta production inhibitors
DE19717371A1 (de) 1997-04-24 1998-10-29 Basf Ag Propargyl-terminierte, nematische oder cholesterische Polymere
WO1999006387A2 (en) 1997-07-31 1999-02-11 F. Hoffmann-La Roche Ag O-substituted hydroxycumaranone derivatives as antitumor and antimetastatic agents
JPH11119379A (ja) 1997-10-08 1999-04-30 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料および画像形成方法
WO1999032447A2 (en) 1997-12-11 1999-07-01 American Home Products Corporation 2,4,6-trisubstituted pyridines with estrogenic activity and methods for the solid phase synthesis thereof
WO2000007978A1 (en) 1998-07-31 2000-02-17 Akzo Nobel N.V. Aminomethylcarboxylic acid derivatives
DE19834751A1 (de) 1998-08-01 2000-02-03 Boehringer Ingelheim Pharma Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel
WO2000023420A1 (fr) 1998-10-20 2000-04-27 Takeda Chemical Industries, Ltd. Derives d'amine aromatique, procede de preparation de ces derives et agents les contenant
WO2000026203A1 (en) 1998-10-30 2000-05-11 Pharmacia & Upjohn S.P.A. 2-ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents
WO2001032178A1 (en) * 1999-10-29 2001-05-10 Novo Nordisk A/S Use of 3,4-substituted piperidines
JP2001233712A (ja) 1999-12-14 2001-08-28 Nippon Kayaku Co Ltd 害虫防除剤
WO2001070731A1 (en) 2000-03-23 2001-09-27 Novartis Ag Decahydro-isoquinolines
WO2001077075A2 (en) 2000-04-06 2001-10-18 Inotek Corporation Inhibitors of inflammation and reperfusion injury
WO2001087293A1 (fr) 2000-05-19 2001-11-22 Takeda Chemical Industries, Ltd. Inhibiteurs de la ?-secretase
WO2002002520A2 (en) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Compounds to treat alzheimer's disease
WO2002002518A2 (en) 2000-06-30 2002-01-10 Elan Pharmaceuticals, Inc. Compounds to treat alzheimer's disease
WO2002034716A2 (en) 2000-10-11 2002-05-02 Merck & Co., Inc. Pyrrolidine modulators of ccr5 chemokine receptor activity
US20020094989A1 (en) 2000-10-11 2002-07-18 Hale Jeffrey J. Pyrrolidine modulators of CCR5 chemokine receptor activity
WO2002066478A1 (en) 2001-02-20 2002-08-29 Astrazeneca Ab Antagonists of gonadotropin releasing hormone
WO2002070510A2 (de) 2001-03-07 2002-09-12 Bayer Aktiengesellschaft Aminodicarbonsäurederivate mit pharmazeutischen eigenschaften
EP1245565A1 (fr) 2001-03-19 2002-10-02 Les Laboratoires Servier Dérivés d'indénoindolones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US6844445B2 (en) 2001-03-19 2005-01-18 Les Laboratoires Servier Indenoindolone compounds
US20020173531A1 (en) 2001-03-19 2002-11-21 Michel Wierzbicki Indenoindolone compounds
WO2002076979A1 (en) 2001-03-27 2002-10-03 Actelion Pharmaceuticals Ltd 1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists
WO2002076964A1 (fr) 2001-03-28 2002-10-03 Sanofi-Synthelabo Derives de n-(arylsulfonyl)beta-aminoacides comportant un groupe aminomethyle substitue, leur procede de preparation et les compositions pharmaceutiques en contenant
WO2002083673A1 (en) 2001-04-10 2002-10-24 Ortho-Mcneil Pharmaceutical, Inc. 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1 receptor mediated disorders
WO2002088089A1 (fr) 2001-04-19 2002-11-07 Banyu Pharmaceutical Co., Ltd. Derives de spiropiperidine, antagonistes du recepteur de nociceptine les contenant en tant qu'ingredient actif et compositions medicinales
WO2002098869A2 (en) 2001-06-05 2002-12-12 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-disubstituted benzo-fused cycloalkyl urea compounds
WO2002100813A2 (en) 2001-06-07 2002-12-19 Eli Lilly And Company Modulators of peroxisome proliferator activated receptors
US6887868B2 (en) 2001-09-21 2005-05-03 Pharmacia & Upjohn Company Therapeutic 5-HT ligand compounds
WO2003035076A1 (en) 2001-10-26 2003-05-01 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dihydroxypyrimidine carboxamide inhibitors of hiv integrase
WO2003037887A1 (en) 2001-11-01 2003-05-08 Astrazeneca Ab Therapeutic isoquinoline compounds
WO2003044016A1 (en) 2001-11-20 2003-05-30 Eli Lilly And Company 3-SUBSTITUTED OXINDOLE β3 AGONISTS
WO2003044017A1 (en) 2001-11-20 2003-05-30 Eli Lilly And Company Beta 3 adrenergic agonists
WO2003066613A1 (en) 2002-02-07 2003-08-14 Novartis Ag N-phenyl-2-pyrimidine-amine derivatives
WO2003084916A2 (en) 2002-04-05 2003-10-16 Warner-Lambert Company Llc Compounds that modulate ppar activity and methods for their preparation
WO2004011430A1 (ja) 2002-07-25 2004-02-05 Yamanouchi Pharmaceutical Co., Ltd. ナトリウムチャネル阻害剤
EP1388342A1 (en) 2002-08-07 2004-02-11 Aventis Pharma Deutschland GmbH Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals
WO2004014372A1 (en) 2002-08-07 2004-02-19 Aventis Pharma Deutschland Gmbh Acylated, heteroaryl-condensed cycloalkenylamines and their use as pharmaceuticals
WO2004022558A2 (en) 2002-09-09 2004-03-18 Janssen Pharmaceutica, N.V. Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of orl-1 receptor mediated disorders
WO2004035579A1 (ja) 2002-10-15 2004-04-29 Takeda Pharmaceutical Company Limited イミダゾピリジン誘導体、その製造法および用途
US20040158067A1 (en) * 2002-11-08 2004-08-12 Neurogen Corporation 3-substituted-6-aryl pyridines
WO2004048363A1 (ja) 2002-11-22 2004-06-10 Takeda Pharmaceutical Company Limited イミダゾール誘導体、その製造法および用途
WO2004052846A1 (en) 2002-12-06 2004-06-24 Bayer Healthcare Ag Tetrahydro-naphthalene derivatives
WO2004058679A2 (en) 2002-12-20 2004-07-15 Migenix Corp. Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto
WO2004078731A1 (fr) 2003-03-06 2004-09-16 'chemical Diversity Research Institute', Ltd. Acides quinoline-carboxyliques et leurs derives et bibliotheque focalisee
US20040229160A1 (en) 2003-03-11 2004-11-18 Arch Specialty Chemicals, Inc. Novel photosensitive resin compositions
WO2004109400A2 (en) 2003-03-11 2004-12-16 Arch Speciality Chemicals, Inc. Novel photosensitive resin compositions
JP2005060247A (ja) 2003-08-12 2005-03-10 Takeda Chem Ind Ltd イソキノリノン誘導体、その製造法および用途
US20060270686A1 (en) 2003-08-29 2006-11-30 Martha Kelly Anti-cancer agents and uses thereof
US20050096336A1 (en) * 2003-11-05 2005-05-05 Jean Ackermann Benzannelated derivatives, their manufacture and use as pharmaceutical agents
WO2005058823A1 (ja) 2003-12-17 2005-06-30 Takeda Pharmaceutical Company Limited ウレア誘導体、その製造法及び用途
US20050159334A1 (en) 2004-01-16 2005-07-21 Gluck Oscar S. Method for treating rheumatoid arthritis by inhibiting peptidylarginine deiminase
WO2005092899A1 (en) 2004-03-26 2005-10-06 Methylgene Inc. Inhibitors of histone deacetylase
US20050228014A1 (en) 2004-04-07 2005-10-13 Theravance, Inc. Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
WO2005100350A1 (en) 2004-04-07 2005-10-27 Theravance, Inc. Quinolinone-carboxamide compounds as 5-ht4 receptor agonists
WO2005105805A1 (fr) 2004-04-29 2005-11-10 'chemical Diversity Research Institute', Ltd. Carbamoylase-heterocycles anneles, bibliotheque focalisee, compositions pharmaceutiques et procedes de fabrication correspondants
WO2005123703A2 (en) 2004-06-17 2005-12-29 Addex Pharmaceuticals Sa Alkynyl derivatives as modulators of metabotropic glutamate receptors
US20070219218A1 (en) 2004-07-16 2007-09-20 Schering Corporation Compounds for the treatment of inflammatory disorders
WO2006048330A1 (en) 2004-11-08 2006-05-11 Evotec Ag 11βετα-hsd1 inhibitors
WO2006062224A1 (ja) 2004-12-07 2006-06-15 Takeda Pharmaceutical Company Limited カルボキサミド誘導体
WO2006069125A1 (en) 2004-12-22 2006-06-29 Theravance, Inc. Indazole-carboxamide compounds
WO2006102588A1 (en) 2005-03-24 2006-09-28 Renovis, Inc. Bicycloheteroaryl compounds as p2x7 modulators and uses thereof
WO2006105971A1 (de) 2005-04-08 2006-10-12 Grünenthal GmbH Substituierte 5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyridin-2-ylamin-verbindungen und deren verwendung zur herstellung von arzneimitteln
WO2006125119A1 (en) 2005-05-17 2006-11-23 Sarcode Corporation Compositions and methods for treatment of eye disorders
WO2006126939A1 (en) 2005-05-23 2006-11-30 Astrazeneca Ab Novel 8-sulfonylamino-3 aminosubstituted chroman or tetrahydronaphtalene derivatives modulating the 5ht6 receptor
WO2006130707A2 (en) 2005-06-02 2006-12-07 Jenrin Discovery Mao-b inhibitors useful for treating obesity
WO2006133104A2 (en) 2005-06-07 2006-12-14 Theravance, Inc. Benzoimidazolone-carboxamide compounds as 5-ht4 receptor agonists
WO2007073503A2 (en) 2005-12-21 2007-06-28 Bristol-Myers Squibb Company Indane modulators of glucocorticoid receptor, ap-1, and/or nf-kb activity and use thereof
WO2007087548A2 (en) 2006-01-25 2007-08-02 Smithkline Beecham Corporation Chemical compounds
US20070191371A1 (en) 2006-02-14 2007-08-16 Kalypsys, Inc. Heterocyclic modulators of ppar
WO2007106469A2 (en) 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
WO2007105989A2 (en) 2006-03-14 2007-09-20 Ivashchenko, Andrey Alexandrovich 1-oxo-3-(1h-indole)-3-il-1,2,3,4-tetrahydroisoxynolines, methods for the production thereof, combinatoric library and focused library
WO2007133108A1 (fr) 2006-05-12 2007-11-22 Chemdiv, Ink. Composition pharmaceutique, procédé de fabrication et d'application
US20080280891A1 (en) 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
WO2008000408A1 (en) 2006-06-28 2008-01-03 Sanofi-Aventis Cxcr2 antagonists
WO2008008059A1 (en) 2006-07-12 2008-01-17 Locus Pharmaceuticals, Inc. Anti-cancer agents ans uses thereof
WO2008022945A1 (de) 2006-08-19 2008-02-28 Boehringer Ingelheim International Gmbh Arylsulfonamide mit analgetischer wirkung
WO2008051757A1 (en) 2006-10-20 2008-05-02 Irm Llc Compositions and methods for modulating c-kit and pdgfr receptors
WO2008064320A2 (en) 2006-11-21 2008-05-29 University Of Virginia Patent Foundation Hydrindane analogs having sphingosine 1-phosphate receptor agonist activity
WO2008066789A2 (en) 2006-11-27 2008-06-05 H. Lundbeck A/S Heteroaryl amide derivatives
WO2008065500A2 (en) 2006-11-30 2008-06-05 Pfizer Products Inc. Heteroaryl amides as type i glycine transport inhibitors
WO2008079988A2 (en) 2006-12-22 2008-07-03 Novartis Ag Quinazolines for pdk1 inhibition
WO2008104077A1 (en) 2007-02-28 2008-09-04 Methylgene Inc. Small molecule inhibitors of protein arginine methyltransferases (prmts)
US20090069373A1 (en) 2007-02-28 2009-03-12 Wyeth Quinoline Acids
WO2008112715A2 (en) 2007-03-12 2008-09-18 Vm Discovery Inc. Novel agents of calcium ion channel modulators
WO2008121687A2 (en) 2007-03-28 2008-10-09 Array Biopharma Inc. Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors
WO2008123582A1 (ja) 2007-04-04 2008-10-16 Kowa Company, Ltd. テトラヒドロイソキノリン化合物
JP2008280344A (ja) 2007-04-12 2008-11-20 Sumitomo Chemical Co Ltd ヒドラジド化合物及びそれを含有する有害節足動物防除剤
WO2008135526A1 (en) 2007-05-02 2008-11-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides as factor xa inhibitors
WO2009038842A2 (en) 2007-06-15 2009-03-26 Mission Pharmacal Co. Methods and compositions to inhibit edema factor and adenylyl cyclase
WO2008156142A1 (ja) 2007-06-20 2008-12-24 Mitsubishi Tanabe Pharma Corporation 新規なマロン酸スルホンアミド誘導体およびその医薬用途
WO2009010925A2 (en) 2007-07-17 2009-01-22 Alla Chem, Llc Annelated azaheterocyclic amides containing a pyrimidine fragment and method for the production and use thereof
WO2009023179A2 (en) 2007-08-10 2009-02-19 Genelabs Technologies, Inc. Nitrogen containing bicyclic chemical entities for treating viral infections
WO2009048152A2 (en) 2007-10-11 2009-04-16 Sumitomo Chemical Company, Limited Unsaturated imine compound and use thereof for pest control
WO2009054914A1 (en) 2007-10-19 2009-04-30 Sarcode Corporation Compositions and methods for treatment of diabetic retinopathy
WO2009080351A1 (en) 2007-12-21 2009-07-02 Santhera Pharmaceuticals (Schweiz) Ag Compounds with anti-emetic effect
US8642660B2 (en) 2007-12-21 2014-02-04 The University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2009112651A1 (fr) 2008-01-02 2009-09-17 Sanofi-Aventis Dérivés d'mtoazo[1,2-a]pyridine-2-carboxamides, leur préparation et leur application en thérapeutique
RU2371444C1 (ru) 2008-01-24 2009-10-27 Андрей Александрович Иващенко ФУРО- И ТИЕНО[2,3-b]-ХИНОЛИН-2-КАРБОКСАМИДЫ, СПОСОБ ПОЛУЧЕНИЯ И ПРОТИВОТУБЕРКУЛЕЗНАЯ АКТИВНОСТЬ
WO2009104819A1 (en) 2008-02-22 2009-08-27 Otsuka Pharmaceutical Co., Ltd. Benzodiazepine compound and pharmaceutical composition
JP2009209090A (ja) 2008-03-04 2009-09-17 Mitsui Chemicals Inc 殺虫剤及び該殺虫剤に含まれる化合物、並びに該化合物の使用方法
US20090264433A1 (en) 2008-04-21 2009-10-22 Institute For Oneworld Health Compounds, Compositions and Methods Comprising Triazine Derivatives
WO2009137309A2 (en) 2008-05-01 2009-11-12 Travel Tech Systems, Llc Process and system to determine commercial airline arrivals
US8148408B2 (en) 2008-05-09 2012-04-03 Abbott Laboratories Selective substituted pyridine ligands for neuronal nicotinic receptors
WO2009140101A2 (en) 2008-05-12 2009-11-19 Boehringer Ingelheim International Gmbh Imidazopyridine compounds useful as mmp-13 inhibitors
JP2009274984A (ja) 2008-05-14 2009-11-26 Sumitomo Chemical Co Ltd 化合物、光学フィルムおよび光学フィルムの製造方法
WO2009153313A1 (en) 2008-06-20 2009-12-23 Novartis Ag 2 -arylaminoquinazolines for treating proliferative diseases
WO2010048207A2 (en) 2008-10-21 2010-04-29 Metabolex, Inc. Aryl gpr120 receptor agonists and uses thereof
EP2194035A2 (de) 2008-12-06 2010-06-09 Saltigo GmbH Hydroxytetralone
WO2010077680A2 (en) 2008-12-08 2010-07-08 Vm Discovery Inc. Compositions of protein receptor tyrosine kinase inhibitors
WO2010075973A1 (de) 2008-12-17 2010-07-08 Grünenthal GmbH Substituierte 4-(1,2,3,4-tetrahydroisochinolin-2-yl)-4-oxo-buttersäureamide als kcnq2/3 modulatoren
WO2010091409A1 (en) 2009-02-09 2010-08-12 Glaxosmithkline Llc Certain nitrogen containing bicyclic chemical entities for treating viral infections
WO2010098495A1 (en) 2009-02-26 2010-09-02 Eisai R&D Management Co., Ltd. Imidazolylpyrazine derivatives
CN101838264A (zh) 2009-03-16 2010-09-22 住友化学株式会社 化合物、光学膜和光学膜的制造方法
JP2011207765A (ja) 2009-03-16 2011-10-20 Sumitomo Chemical Co Ltd 化合物、光学フィルム及び光学フィルムの製造方法
US20100249127A1 (en) 2009-03-31 2010-09-30 Arqule, Inc. Substituted indolo-pyridinone compounds
WO2010151799A2 (en) 2009-06-26 2010-12-29 University Of Massachusetts Compounds for modulating rna binding proteins and uses therefor
JP2011063589A (ja) 2009-08-21 2011-03-31 Otsuka Pharmaceut Co Ltd 医薬組成物
WO2011023989A1 (en) 2009-08-24 2011-03-03 Sterix Limited Aromatase inhibitor
WO2011086178A1 (en) 2010-01-15 2011-07-21 Hybrigenics Sa Amidoacridine derivatives useful as selective inhibitors of ubiquitin specific protease 7
WO2011100380A1 (en) 2010-02-11 2011-08-18 Celgene Corporation Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same
WO2011123751A2 (en) 2010-04-02 2011-10-06 Amgen Inc. Heterocyclic compounds and their uses
WO2012006202A1 (en) 2010-07-07 2012-01-12 Boehringer Ingelheim International Gmbh Rho kinase inhibitors
WO2012006203A1 (en) 2010-07-07 2012-01-12 Boehringer Ingelheim International Gmbh N-cyclyl-3 - (cyclylcarbonylaminomethyl) benzamide derivatives as rho kinase inhibitors
WO2012022045A1 (en) 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
WO2012022265A1 (en) 2010-08-20 2012-02-23 Hutchison Medipharma Limited Pyrrolopyrimidine compounds and uses thereof
WO2012058133A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. Isoindolinone pde10 inhibitors
WO2012087833A1 (en) 2010-12-22 2012-06-28 Abbott Laboratories Hepatitis c inhibitors and uses thereof
WO2013002879A1 (en) 2011-06-29 2013-01-03 President And Fellows Of Harvard College Small molecule cd38 inhibitors and methods of using same
WO2013002880A1 (en) 2011-06-29 2013-01-03 The General Hospital Corporation Compositions and methods for enhancing bioenergetic status in female germ cells
WO2013000994A1 (en) 2011-06-30 2013-01-03 Abbott Gmbh & Co. Kg Novel inhibitor compounds of phosphodiesterase type 10a
WO2013018371A1 (ja) 2011-08-03 2013-02-07 杏林製薬株式会社 ビアリールエステル誘導体、及びそれを含む医薬
WO2013025733A1 (en) 2011-08-15 2013-02-21 Intermune, Inc. Lysophosphatidic acid receptor antagonists
US9732066B2 (en) 2011-08-18 2017-08-15 Nippon Shiny Aku Co., Ltd. Heterocyclic derivative and pharmaceutical drug
RU2632908C2 (ru) 2011-08-18 2017-10-11 Ниппон Синяку Ко., Лтд. Гетероциклическое производное и фармацевтическое средство
WO2013068470A1 (en) 2011-11-09 2013-05-16 Abbott Gmbh & Co. Kg Inhibitors of phosphodiesterase type 10a
WO2013096681A1 (en) 2011-12-22 2013-06-27 Gilead Sciences, Inc. Pyrazolo[1,5-a]pyrimidines as antiviral agents
WO2013096055A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096059A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096049A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013096060A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
WO2013120464A1 (en) 2012-02-17 2013-08-22 Zentiva, K.S. A process for the preparation of rivaroxaban based on saving of 1,1'-carbonyl diimidazole.
WO2013127729A1 (en) 2012-02-27 2013-09-06 Boehringer Ingelheim International Gmbh 6 - alkynyl pyridines as smac mimetics
WO2013174895A1 (en) 2012-05-24 2013-11-28 Cellzome Limited Heterocyclyl pyrimidine analogues as tyk2 inhibitors
WO2013178810A1 (en) 2012-05-31 2013-12-05 Universite De Strasbourg Ornithine- and lysine-derivatives for the treatment of pain
WO2013192430A2 (en) 2012-06-20 2013-12-27 The Regents Of The University Of California Dynamic biomimetic synzyme catalyst, catalysis, and catalytic systems
WO2014013182A1 (fr) 2012-07-20 2014-01-23 Metabrain Research Derive d'imidazopyridine utiles dans le traitement du diabete
WO2014015905A1 (en) 2012-07-26 2014-01-30 Glaxo Group Limited 2 - (azaindol- 2 -yl) benz imidazoles as pad4 inhibitors
WO2014031872A2 (en) 2012-08-23 2014-02-27 The Broad Institute, Inc. Small molecule inhibitors for treating parasitic infections
WO2014031986A1 (en) 2012-08-24 2014-02-27 Board Of Regents Of The University Of Texas System Pro-neurogenic compounds
WO2014077321A1 (ja) 2012-11-15 2014-05-22 高砂香料工業株式会社 アルミニウム触媒
WO2014100719A2 (en) 2012-12-21 2014-06-26 Epizyme, Inc. Prmt5 inhibitors and uses thereof
WO2014100764A2 (en) 2012-12-21 2014-06-26 Epizyme, Inc. Methods of inhibiting prmt5
WO2014152018A1 (en) 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US20160229816A1 (en) * 2013-07-17 2016-08-11 Otsuka Pharmaceutical Co., Ltd. Cyanotriazole compounds
WO2015011397A1 (fr) 2013-07-23 2015-01-29 Les Laboratoires Servier Nouveaux dérivés d'indolizine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2015031295A1 (en) 2013-08-27 2015-03-05 Bristol-Myers Squibb Company Ido inhibitors
WO2015034820A1 (en) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
US20160194307A1 (en) * 2013-09-04 2016-07-07 Bristol-Myers Squibb Company Compounds useful as immunomodulators
WO2015086512A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of tnf activity
WO2015086527A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused tricyclic imidazole derivatives as modulators of tnf activity
WO2015108038A1 (ja) 2014-01-17 2015-07-23 第一三共株式会社 エチレングリコール化合物
EP3112362A1 (en) 2014-02-27 2017-01-04 ONO Pharmaceutical Co., Ltd. Compound exhibiting selective ep2 agonist activity
US9067898B1 (en) 2014-03-07 2015-06-30 Janssen Pharmaceutica Nv Isothiazole derivatives as GPR120 agonists for the treatment of type II diabetes
WO2015140051A1 (en) 2014-03-19 2015-09-24 Boehringer Ingelheim International Gmbh Heteroaryl sik inhibitors
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
WO2016008433A1 (en) 2014-07-17 2016-01-21 Sunshine Lake Pharma Co., Ltd. Substituted urea derivatives and pharmaceutical uses thereof
WO2016031815A1 (ja) 2014-08-26 2016-03-03 武田薬品工業株式会社 複素環化合物
WO2016034675A1 (en) 2014-09-03 2016-03-10 Ctxt Pty Ltd Tetrahydroisoquinoline derived prmt5-inhibitors
WO2016036636A1 (en) 2014-09-05 2016-03-10 Merck Sharp & Dohme Corp. Tetrahydroisoquinoline derivatives useful as inhibitors of diacylglyceride o-acyltransferase 2
CN105461693A (zh) 2014-09-26 2016-04-06 广东东阳光药业有限公司 Crth2拮抗剂化合物及其用途
WO2016051306A2 (en) 2014-10-03 2016-04-07 Maheshwari Divya Novel anthranilic acid derivatives
WO2016102727A1 (es) 2014-12-22 2016-06-30 Consejo Superior De Investigaciones Científicas (Csic) Compuestos moduladores del sensor neuronal de calcio dream y sus usos terapéuticos
WO2016185279A1 (en) 2015-05-21 2016-11-24 Glaxosmithkline Intellectual Property Development Limited Benzoimidazole derivatives as pad4 inhibitors
US20170105971A1 (en) 2015-07-03 2017-04-20 Anca CATRINA Methods and compounds for the treatment of bone loss and/or pain
WO2017024180A1 (en) 2015-08-06 2017-02-09 Amgen Inc. Vinyl fluoride cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2017025510A1 (en) 2015-08-12 2017-02-16 Syngenta Participations Ag Microbiocidal heterobicyclic derivatives
WO2017042182A1 (en) 2015-09-08 2017-03-16 F. Hoffmann-La Roche Ag Tricyclic pi3k inhibitor compounds and methods of use
WO2017068412A1 (en) 2015-10-21 2017-04-27 Otsuka Pharmaceutical Co., Ltd. Benzolactam compounds as protein kinase inhibitors
WO2017106634A1 (en) 2015-12-17 2017-06-22 Incyte Corporation N-phenyl-pyridine-2-carboxamide derivatives and their use as pd-1/pd-l1 protein/protein interaction modulators
WO2017109095A1 (en) 2015-12-22 2017-06-29 AbbVie Deutschland GmbH & Co. KG Fused (hetero)cyclic compounds as s1p modulators
US20170174672A1 (en) 2015-12-22 2017-06-22 AbbVie Deutschland GmbH & Co. KG Fused (hetero)cyclic compounds as s1p modulators
WO2017118762A1 (en) 2016-01-08 2017-07-13 Rijksuniversiteit Groningen Inhibitors of the pd-1/pd-l1 protein/protein interaction
WO2017147102A1 (en) 2016-02-23 2017-08-31 Padlock Therapeutics, Inc. Heteroaryl inhibitors of pad4
WO2017216281A1 (en) 2016-06-16 2017-12-21 Janssen Sciences Ireland Uc Heterocyclic compounds as antibacterials
WO2018002848A1 (en) 2016-06-30 2018-01-04 VIIV Healthcare UK (No.5) Limited Azadecalin derivatives as inhibitors of human immunodeficiency virus replication
WO2018019204A1 (zh) 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物
WO2018026971A1 (en) 2016-08-03 2018-02-08 Arising International, Llc Symmetric or semi-symmetric compounds useful as immunomodulators
WO2018119036A1 (en) 2016-12-21 2018-06-28 Janssen Biotech, Inc. Pyrazole derivatives as malt1 inhibitors
WO2018112843A1 (en) 2016-12-22 2018-06-28 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor
WO2018121610A1 (zh) 2016-12-27 2018-07-05 山东大学 针对Smoothened突变株的刺猬通路抑制剂
CN107056630A (zh) 2017-01-23 2017-08-18 合肥工业大学 一种茚满类衍生物及其合成方法和在医药上的用途
WO2018183411A1 (en) 2017-03-28 2018-10-04 The Regents Of The University Of Michigan Small molecule dcn1 inhibitors and therapeutic methods using the same
WO2018208985A2 (en) 2017-05-10 2018-11-15 Forge Therapeutics, Inc. Antibacterial compounds
CN107163044A (zh) 2017-06-19 2017-09-15 广东药科大学 一类具有蛋白酶修饰活性的萘乙二酮化合物及其衍生物
WO2018234342A1 (en) 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag ISOINDOLINONE DERIVATIVES AS MODULATORS OF IRAK4
WO2019007696A1 (en) 2017-07-06 2019-01-10 Galapagos Nv NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF FIBROSIS
WO2019058393A1 (en) 2017-09-22 2019-03-28 Jubilant Biosys Limited HETEROCYCLIC COMPOUNDS AS INHIBITORS OF PAD
WO2019077631A1 (en) 2017-10-18 2019-04-25 Jubilant Biosys Limited IMIDAZO-PYRIDINE COMPOUNDS FOR USE AS PAD INHIBITORS
WO2019079783A1 (en) 2017-10-20 2019-04-25 Vanderbilt University ANTAGONISTS OF THE MUSCARINIC RECEPTOR OF ACETYLCHOLINE M4
WO2019087214A1 (en) 2017-11-06 2019-05-09 Jubilant Biosys Limited Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation
US20210179580A1 (en) * 2017-11-06 2021-06-17 Jubilant Prodel LLC Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation
US20210371431A1 (en) 2017-11-24 2021-12-02 Jubilant Episcribe Llc Heterocyclic compounds as prmt5 inhibitors
WO2019102494A1 (en) 2017-11-24 2019-05-31 Jubilant Biosys Limited Heterocyclic compounds as prmt5 inhibitors
WO2019126081A1 (en) 2017-12-19 2019-06-27 Bristol-Myers Squibb Company Amide substituted indole compounds useful as tlr inhibitors
WO2019154047A1 (zh) 2018-02-07 2019-08-15 复旦大学 烷氧基苯并五元(六元)杂环胺类化合物及其药物用途
WO2019160014A1 (ja) 2018-02-14 2019-08-22 富士フイルム株式会社 重合性液晶組成物、光学異方性膜、光学フィルム、偏光板および画像表示装置
US11230526B1 (en) * 2018-03-06 2022-01-25 Janssen Pharmaceutica Nv Cylcoalkenyl derivatives useful as agonists of the GPR120 and/or GPR40 receptors
WO2019175897A1 (en) 2018-03-13 2019-09-19 Jubilant Biosys Limited Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation
JP2019156770A (ja) 2018-03-14 2019-09-19 日本化薬株式会社 ベンゾアゾール化合物、並びにこれを含んだ顔料組成物
CN108358917A (zh) 2018-04-24 2018-08-03 北京市结核病胸部肿瘤研究所 含有碱性稠环片段的咪唑并[1,2-a]吡啶-3-酰胺类化合物及其制备方法
WO2019205147A1 (zh) 2018-04-28 2019-10-31 上海璃道医药科技有限公司 包含苯并含氧脂肪环结构的氨基乙酰胺类化合物及其用途
WO2019213234A1 (en) 2018-05-01 2019-11-07 The Trustees Of Columbia University In The City Of New York Triazolopyrimidines, their preparation and use
WO2020028723A1 (en) 2018-08-01 2020-02-06 The Trustees Of Columbia University In The City Of New York Rbp4 antagonists for treatment and prevention of non-alcoholic fatty liver disease and gout
WO2020029980A1 (en) 2018-08-06 2020-02-13 Moexa Pharmaceuticals Limited Smad3 inhibitors
WO2020045216A1 (ja) 2018-08-28 2020-03-05 富士フイルム株式会社 積層体および画像表示装置
CN110963997A (zh) 2018-09-28 2020-04-07 四川科伦博泰生物医药股份有限公司 杂环酰胺类化合物、包含其的药物组合物及其制备方法和用途
WO2020083971A2 (en) 2018-10-24 2020-04-30 Bayer Animal Health Gmbh New anthelmintic compounds
WO2020092394A1 (en) 2018-10-30 2020-05-07 Gilead Sciences, Inc. Imidazopyridine derivatives as alpha4beta7 integrin inhibitors
CN110105299A (zh) 2019-01-23 2019-08-09 中山大学 一种含芳醚取代恶唑烷酮羧酸酯类衍生物及其制备方法和应用
WO2020201773A1 (en) 2019-04-05 2020-10-08 Storm Therapeutics Ltd Mettl3 inhibitory compounds
WO2020246910A1 (ru) 2019-06-03 2020-12-10 Александл Васильевич ИВАЩЕНКО АНЕЛИРОВАННЫЕ 9-ГИДРОКСИ- 1,8 - ДИОКСО- 1, 3,4, 8 -ТЕТРАГИДРО-2Н-ПИРИДО [1,2-α] ПИРАЗИН-7 - КАРБОКСАМИДЫ - ИНГИБИТОРЫ ИНТЕГРАЗЫ ВИЧ
WO2021014949A1 (ja) 2019-07-24 2021-01-28 住友化学株式会社 重合性液晶混合組成物、位相差板、楕円偏光板および有機ｅｌ表示装置
WO2021018858A1 (en) 2019-07-29 2021-02-04 Les Laboratoires Servier 6,7-dihydro-5h-pyrido[2,3-c]pyridazine derivatives and related compounds as bcl-xl protein inhibitors and pro-apoptotic agents for treating cancer
WO2021028810A1 (en) 2019-08-09 2021-02-18 Inorbit Therapeutics Ab Sulfinic acid compounds as free fatty acid receptor agonists
JP2021054909A (ja) 2019-09-27 2021-04-08 富士フイルム株式会社 液晶組成物、光学異方性層、光学フィルム、偏光板および画像表示装置
WO2021060432A1 (ja) 2019-09-27 2021-04-01 富士フイルム株式会社 液晶組成物、光学異方性層、光学フィルム、偏光板および画像表示装置
WO2021096241A1 (en) 2019-11-15 2021-05-20 Yuhan Corporation Novel compounds having inhibitory activity against glucosylceramide synthase or pharmaceutically acceptable salt thereof, processes for preparing the same, and pharmaceutical compositions comprising the same
WO2021096238A1 (en) 2019-11-15 2021-05-20 Yuhan Corporation Novel derivatives having 2,3-dihydro-1h-indene or 2,3-dihydrobenzofuran moiety or pharmaceutically acceptable salt thereof and pharmaceutical compositions comprising the same
CN111606904A (zh) 2020-04-07 2020-09-01 广州医科大学 氮杂吲哚类化合物及其应用

Non-Patent Citations (92)

* Cited by examiner, † Cited by third party
Title
"Letter to the Editors-in-Chief", Thrombosis Research 191, pp. 26-27, 2020.
Acharya et al., "Neuronal PAD4 expression and protein citrullination: Possible role in production of autoantibodies associated with neurodegenerative disease", J. Autoimmun., vol. 38, pp. 369-380, 2012.
Arisan, et al., "Putative Roles for Peptidylarginine Deiminases in COVID-19", International Journal of Molecular Sciences, vol. 21, No. 13, in 29 pages, 2020.
Barber, et al., "Restoring function in exhausted CD8 T cells during chronic viral infection", Nature, vol. 439, No. 7077, pp. 682-687, 2005.
Bardhan, et al., "The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation", Frontiers in Immunology, vol. 7, No. 550, pp. 1-17, 2016.
Barnes, et al., "Targeting potential drivers of COVID-19: Neutrophil extracellular traps", Journal of Experimental Medicine, vol. 217, No. 6, in 7 pages, 2020.
Bertini, et al., "Carbazole-containing arylcarboxamides as BACE1 inhibitors," Bioorganic & Medicinal Chemistry Letters (2011), 21 (22), 6657-6661.
Borregaard, "Neutrophils, from Marrow to Microbes", Immunity, vol. 33, No. 5, pp. 657-670, 2010.
Brinkmann, et al., "Neutrophil Extracellular Traps Kill Bacteria", Science, vol. 303, No. 5663, pp. 1532-1535, 2004.
Candi et al., "The Cornified Envelope: A Model of Cell Death in the Skin", Nat. Rev. Mol. Cell Biol., vol. 6, pp. 328-340, 2005.
Cedervall et al., NETosis in Cancer, Oncoscience, vol. 2, No. 11, pp. 900-901, 2015.
Chang et al., "Increased PADI4 expression in blood and tissues of patients with malignant tumors", BMC Cancer, vol. 9, pp. 40, 2009.
Chemical Abstracts STN Registry Database, Record for RN 1648388-87-7, Entered into STN Feb. 16, 2015. (Year: 2015). *
Chen, et al., "Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future", Journal of Clinical Investigation, vol. 125, No. 9, pp. 3384-3391, 2015.
Chiummiento, et a;., "New indolic non-peptidic HIV protease inhibitors from (S)-glycidol: synthesis and preliminary biological activity," Tetrahedron (2009), 65(31), 5984-5989.
Christophorou et al., Citrullination regulated pluripotency and histone H1 binding to chromatin, Nature, vol. 507, pp. 104-108, 2014.
Chumanevich et al., "Suppression of colitis in mice by C1-amidine: a novel peptidylarginine deiminase inhibitor", Am. J. Physiol. Gastrointest. Liver Physiol., vol. 300, No. 6, pp. G929-G938, 2011.
Cromwell, et al., "Amino ketones. III. B-Tetrahydroisoquinolino ketones and derivatives. Reaction with Grignard reagents," Journal of the American Chemical Society (1944), 66, 872-3.
Curiel, et al., "Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor or immunity", Nature Medicine, vol. 9, No. 5, pp. 562-567, 2003.
Dimauro et al., Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitor of Lck: Synthesis, SAR, and in Vivo Anti-inflammatory Activity, Journal of Medical Chemistry, vol. 49, No. 19, pp. 5671-5686, 2006.
Dong, et al., "PD-1 and its ligands are important immune checkpoints in cancer", Oncotarget, vol. 8, No. 2, pp. 2171-2186, 2017.
Dong, et al., "Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion", Nature Medicine, vol. 8, No. 8, pp. 793-800, 2002.
Evans, et al. "Phenoxyacetic acids as PPAR□ partial agonists: Synthesis, optimization, and in vivo efficacy," Bioorganic & Medicinal Chemistry Letters (2011), 21(8), 2345-2350.
First Examination Report dated Sep. 8, 2021 received in Indian Patent Application No. 201741033768.
Flies, et al., "Blockade of the B7-H1/PD-1 Pathway for Cancer Immunotherapy", Yale J. Biology Medicine, vol. 84, No. 4, pp. 409-421, 2011.
Flies, et al., "The New B7S: Playing a Pivotal Rose in Tumor Immunity", Immunotherapy, vol. 30, No. 3, pp. 251-260, 2007.
Francisco, et al., "PD-L1 regulates the development, maintenance, and function of induced regulatory T cells", Journal of Experimental Medicine, vol. 206, No. 13, pp. 3015-3029, 2009.
Fuhrmann, Jakob, et al., "Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation," Chemical Reviews, 2015, 115, 5413-5461.
Fukagawa, Tomokichi, "The biuret reaction. VII. Primary-quaternary bases which give the biuret reaction," Z. physiol. Chem. (1931), 201, 40-6.
Goi, et al., "Synthesis and pharmacological properties of pyridinecarbonyl derivatives of 7-substituted theophyllines," Chimica Therapeutica (1973), 8(6), 634-7.
Guo, et al., "Development of Benzophenone-Alkyne Bifunctional Sigma Receptor Ligands," ChemBioChem (2012), 13(15), 2277-2289.
Gyorgy et al., "Citrullination: A posttranslational modification in health and disease", Int. J. Biochem. Cell Biol., vol. 38, pp. 1662-1677, 2006.
Hamanishi, et al., "PD-1/PD-L1 blockade in cancer treatment: perspectives and issues", Int. J. Clin. Oncol., vol. 21, pp. 462-473, 2016.
Hankovsky, et al., "New antiarrhythmic agents. 2,2,5,5-Tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5 tetramethylpyrrolidine-3-carboxamides," Journal of Medicinal Chemistry (1986), 29(7), 1138-52.
He, et al., "Development of PD-1/PD-L1 Pathway in Tumor Immune Microenvironment and Treatment for Non-Small Cell Lung Cancer", Scientific Reports, vol. 5, pp. 1-9, 2015.
Hwang, et al., "Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction," Bioorganic & Medicinal Chemistry Letters (2013), 23(6), 1891-1895.
International Search Report & written opinion, dated Feb. 14, 2019, in International Application No. PCT/IN2018/050671.
International Search Report & Written Opinion, dated Feb. 20, 2019, in International Application No. PCT/IN2018/050671.
International Search Report and Written Opinion dated Nov. 12, 2018 for PCT/IN2018/050614.
International Search Report dated May 20, 2019 in International Application No. PCT/IN2019/050203.
Ireland et al., "Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells", J. Exp. Med., vol. 208, pp. 2625-2632, 2011.
Ivaschenko, et al., "Synthesis, biological evaluation and in silico modeling of novel integrase strand transfer inhibitors (INSTIs)," European Journal of Medicinal Chemistry (2020), 189, 112064.
Jones et al., "Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential", Curr. Opin. Drug Discov. Devel., vol. 12, pp. 616-627, 2009.
Knight et al., "Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis", Circ. Res., vol. 114, No. 6, pp. 947-956, 2014.
Kochi et al., "PADI4 polymorphism predisposes male smokers to rheumatoid arthritis", Ann. Rheum. Dis., vol. 70, pp. 512-515, 2011.
Labrie, et al., "In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP450," Bioorganic & Medicinal Chemistry (2006), 14(23), 7972-7987.
Lai, et al., "A Novel PD-L1-targeting Antagonistic DNA Aptamer With Antitumor Effects", Mol. Therapy—Nucl. Acids, vol. 5, pp. e397, 2016.
Lakshmann, et al.,"Synthesis and evaluation of novel N-substituted-6 methoxynaphthalene-2-carboxamides as potential chemosensitizing agents for cancer," Chemical & Pharmaceutical Bulletin (2008), 56(7), 894-896.
Lange et al., "Protein deiminases: New players in the developmentally regulated loss of neural regenerative ability", Dev. Biol., vol. 355, No. 2, pp. 205-214, 2011.
Lee, et al., Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-y-induced upregulation of B7-H1 (CD274), FEBS Letters, vol. 580, pp. 755-762, 2006.
Leung, et al., "The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy", Immune Network, vol. 14, No. 6, pp. 265-276, 2014.
Lewis et al, "Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation", Nature Chemical Biology 11(3), 189-191. 10.1038/nchembio.1735, 2015.
Li et al., "Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4", Mol. Cell Biol., vol. 28, pp. 4745-4758, 2008.
Liu, G.-Y, et al., "Overexpression of peptidylarginine deiminase IV features in apoptosis of haematopoietic cells", Apoptosis, vol. 11, pp. 183-196, 2006.
Loos et al., "Citrullination of CXCL10 and CXCL11 by peptidylarginine deiminase: a naturally occurring posttranslational modification of chemokines and new dimension of immunoregulation", Blood, vol. 112, pp. 2648-2656, 2008.
Mahoney; Nat Rev Drug Discov 2015, 14, 561-584. doi: 10.1038/nrd4591. (Year: 2015). *
Makrygiannakis et al., "Citrullination is an inflammation-dependent process", Ann. Rheum. Dis., vol. 65, pp. 1219-1222, 2006.
Mastronardi et al., "Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation", The Journal of Neurosciences, vol. 26, pp. 11387-11396, 2006.
Mohanan, Sunish, et al., "Potential Role of Peptidylarginine Deiminase Enzymes and Protein Citrullination in Cancer Pathogenesis," Biochemistry Research International, vol. 2012, article ID 895343.
Muenst, et al., "Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer", Breast Cancer Res. Treat., vol. 146, No. 1, pp. 15-24, 2014.
Nakashima et al., "Molecular Characterization of Peptidylarginine Deiminase in HL-60 Cells Induced by Retinoic Acid and 1α,25-Dihydroxyvitamin D3", J. Biol. Chem., vol. 274, pp. 27786-27792, 1999.
Nathan, "Neutrophils and COVID-19: Nots, NETs, and knots", The Journal of Experimental Medicine, vol. 217, No. 9, in 3 pages, 2020.
Neeli et al., "Histone Deimination as a Response to Inflammatory Stimuli in Neutrophils", J. Immunol., vol. 180, pp. 1895-1902, 2008.
Nicolaou, et al., "Synthesis of imides, N-acyl vinylogous carbamates and ureas, and nitriles by oxidation of amides and amines with Dess-Martin periodinane," Angewandte Chemie, International Edition (2005), 44(37), 5992-5997.
Omran, et al., "Synthesis and biological evaluation of new Donepezil-like Thiaindanones as AChE inhibitors," Journal of Enzyme Inhibition and Medicinal Chemistry (2008), 23(5), 696-703.
Patsoukis, et al., "PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A", Cell Cycle, vol. 11, No. 23, pp. 4305-4309, 2012.
Piper, et al., "Synthesis of potential inhibitors of hypoxanthine-guanine phosphoribosyltransferase for testing as antiprotozoal agents. 1. 7-Substituted 6-oxopurines," Journal of Medicinal Chemistry (1980), 23(4), 357-64.
Schönrich, et al., "Neutrophil Extracellular Traps Go Viral", Frontiers in Immunology, vol. 7, No. 366 in 7 pages, 2016.
Search Report dated Sep. 2, 2021 in Russian Application No. 2020132944.
Sheppard, et al., "PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3 signalosome and downstream signaling to PKC0", FEBS Letters, vol. 574, pp. 37-41, 2004.
Slack et al., "Protein arginine deiminase 4: a target for an epigenetic cancer therapy", Cellular and Molecular Life Sciences, vol. 68, No. 4, pp. 709-720, 2011.
Smahel, Michal, "PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated MHC Class I Expression", Int. J. Mol. Sci., vol. 18, No. 6, pp. 1331, 2017.
Spassova, et al., "Synthesis of N-(3-azido-2 hydroxypropyl), N-(3-phthalimido-2-hydroxypropyl) and N-(3-amino-2 hydroxypropyl) derivatives of heterocyclic bases," Collection of Czechoslovak Chemical Communications (1994), 59(5), 1153-74.
STN Chemical Abstracts Registry Database, record for RN 1349491-87-7: 2-(4-Bromophenyl)-6-[[(2,3-dihydro-1H-inden-4-yl)oxy]methyl]-4-(1,1-dimethylethyl)-2-morpholinol. Entered STN Dec. 6, 2011. (Year: 2011). *
Topalian, et al., "Targeting the PD-1/B7-H1 (PD-L1) pathway to activate anti-tumor immunity", Curr. Opin. Immunol., vol. 24, No. 2, pp. 207-212, 2012.
Uenishi, et al, "Structural effects of diazonaphthoquinone-photoactivecompound backbone on resist lithographic properties," Proceedings of SPIE—The International Society for Optical Engineering (1991), 1466(Adv. Resist Technol. Process. 8), 102-16.
Vinay, et al., "Immune evasion in cancer: Mechanistic basis and therapeutic strategies", Seminars in Cancer Biology, vol. 35, pp. S185-S198, 2015.
Vooturi, et al., "Solution-phase parallel synthesis of novel membrane-targeted antibiotics," Journal of Combinatorial Chemistry (2010), 12(1), 151-160.
Wang et al., "Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation", J. Cell Biol., vol. 184, pp. 205-213, 2009.
Wang, et al., "PD-LI expression in human cancers and its association with clinical outcomes", Oncotargets and Therapy, vol. 9, pp. 5023-5039, 2016.
Wang, et al., "Prognostic significance of PD-L1 in solid tumor", Medicine Baltimore, vol. 96, No. 18, pp. e6369, 2017.
Wang, Shu, et al., "Peptidylarginine deiminases in citrullination, gene regulation, health and pathogenesis," Biochim Biophys Acta, Oct. 2013; 1829 (10): 1126-1135.
Wei, Lianhu, et al., "Novel Inhibitors of Protein Arginine Deiminase with Potential Activity in Multiple Sclerosis Animal Model," Journal of Medicinal Chemistry, 2013, 56, 1715-1722.
Willis et al., N-α-Benzoyl-N5-(2-Chloro-1-Iminoethyl)-1-Ornithine Amine, a Protein Arginine Deiminase Inhibitor, Reduces the Severity of Murine Collagen-Induced Arthritis, J. Immunol., vol. 186, No. 7, pp. 4396-4404, 2011.
Written Opinion dated May 20, 2019 in International Application No. PCT/IN2019/050203.
Zajdel, et al, "Solid-phase synthesis of aryl-alkylamine derivatives using protected aminoalcohol building blocks on SynPhase lanterns," QSAR & Combinatorial Science (2007), 26(2), 215-219.
Zak; Oncotarget 2016, 7, 30323-30335. https://doi.org/10.18632/oncotarget.8730 (Year: 2016). *
Zamarron, et al., "Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression", Intl. J. Biol. Sciences, vol. 7, No. 5, pp. 651-658, 2011.
Zawrotniak, et al., "Neutrophil extracellular traps (NETs)—formation and implications", ACTA Biochimica Polonica, vol. 60, No. 3, pp. 277-284, 2013.
Zhuravel, et al, "Solution-phase synthesis of a combinatorial library of 3-[4-(Coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides," Molecules (2005), 10(2), 444-456.
Zou, et al., "Neutrophil extracellular traps in COVID-19", JCI Insight, vol. 5, No. 11, pp. 1-11, 2020.
Zou, et al., "PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations", Sci. Transl. Med., vol. 8, No. 328, pp. 328rv4, 2016.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12357639B2 (en) 2017-09-22 2025-07-15 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

Also Published As

Publication number Publication date
MX2020009517A (es) 2021-01-20
CN112105610B (zh) 2024-01-26
RU2020132944A (ru) 2022-04-14
IL277183B1 (en) 2023-04-01
AU2019234185A1 (en) 2020-10-01
SG11202008950PA (en) 2020-10-29
JP7279063B2 (ja) 2023-05-22
BR112020018610A2 (pt) 2020-12-29
CN112105610A (zh) 2020-12-18
JP2021518338A (ja) 2021-08-02
IL277183A (en) 2020-10-29
WO2019175897A1 (en) 2019-09-19
US20210015810A1 (en) 2021-01-21
JP7279063B6 (ja) 2024-02-15
IL277183B2 (en) 2023-08-01
KR20200131845A (ko) 2020-11-24
AU2019234185B2 (en) 2024-08-01
RU2020132944A3 (ja) 2022-04-14
CA3093527A1 (en) 2019-09-19
EP3765453A1 (en) 2021-01-20
ZA202005666B (en) 2021-09-29

Similar Documents

Publication Publication Date Title
US11529341B2 (en) Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US12187743B2 (en) Heterocyclic compounds as immunomodulators
US20240132523A1 (en) Salts and crystalline forms of a pd-1/pd-l1 inhibitor
JP7279057B6 (ja) Ｐｄ１／ｐｄ－ｌ１活性化の阻害剤としてのピリミジン誘導体
CN109400522B (zh) 一种具有pd-l1抑制活性的化合物、其制备方法及用途
US10669271B2 (en) Heterocyclic compounds as immunomodulators
AU2021221887A1 (en) Heterocyclic compounds as immunomodulators
US10703746B2 (en) Mutant IDH1 inhibitors useful for treating cancer
CN111635373B (zh) 多环磺酰胺类RORγ调节剂
US20240246931A1 (en) Compounds as pd1/pd-l1 inhibitors and methods thereof
RU2777980C2 (ru) Бициклические соединения в качестве ингибиторов взаимодействия/активации pd1/pd-l1
RU2783211C2 (ru) Производные пиримидина в качестве ингибиторов активации pd1/pd-l1

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STPP Information on status: patent application and granting procedure in general

Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

AS Assignment

Owner name: JUBILANT PRODEL LLC, PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VENKATESHAPPA, CHANDREGOWDA;D A, JEYARAJ;PENDYALA, MURALIDHAR;AND OTHERS;SIGNING DATES FROM 20221108 TO 20221109;REEL/FRAME:061758/0261

STCF Information on status: patent grant

Free format text: PATENTED CASE